ADDENDUM I_jaarverslag IBB 2010 - Institute Born

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ADDENDUM I_jaarverslag IBB 2010 - Institute Born
ADDENDUM I
FWO ONDERZOEKSPROJECT G.0551.04
EINDVERSLAG SEPTEMBER 2010
Promotor: DE DEYN P.P.
Instituut Born-Bunge
Commissie MED6
Periode onderzoeksproject 1/01/2008 – 1/09/2010
Inclusief update tot 31/12/2010 voor IBB Jaarverslag
Toelage van de Vlaamse Gemeenschap door FWO uitgevoerd.
Scientific Report Institute Born-Bunge 2010. Page 4
1. SCIENTIFIC RESULTS
I.
INTRODUCTION
This report summarizes the scientific results of research in the fields of neurology and cardiology
performed in the periode 2008 till present within the framework of an agreement between the
Research Fund – Flanders, the University of Antwerp and the Institute Born Bunge (IBB). The
previously submitted report described the scientific results of the period 1/Jan 2004 – 31/Dec 2007.
The IBB encompasses the following laboratories: 1) Laboratory of Neuropathology and
Electronmicroscopy (Prof. em. J-J. Martin and Prof. C. Ceuterick); 2) Laboratory of Neurobiology
(Prof. P. Cras) focussing on the study of prion diseases; 3) Laboratory of Neurogenetics (Prof. C.
Van Broeckhoven) focussing on the study of central and periferal nervous system disorders; 4)
Laboratory of Theoretical Neurobiology (Prof. E. De Schutter and Prof. dr. M. Guigliano) focussing
on neuronal computer simulations; 5) Laboratory of Neurochemistry and Behaviour (Prof. P.P. De
Deyn); and 6) Laboratory of Cardiovascular Research (Prof. P.-P. van Bogaert).
Since 2005, Prof. P.P. De Deyn is Scientific director of the IBB, and in 2006, a new organigram was
implemented to further support the expansion of the Biobank Central Core Facility; the Laboratory
for Ultrastructural Neuropathology was established and three task forces were defined: 1)
Neuromuscular Diseases; 2) Prion Diseases, and 3) Central Nervous system Neurodegenerative
Disorders.
II.
II.1
STUDY OF DEMENTIA AND THE ESTABLISHMENT OF A BRAIN BANK
From the Laboratory of Neurochemistry and Behaviour (P.P. De Deyn, S. Engelborghs and
co-workers)
A. Improved characterisation of the MCI and Dementia study population:
This research project led to a better clinical, behavioural and neuropsychological characterisation of
the dementia population included (across diagnostic categories).
A cross-sectional analysis of frontal lobe features, behavioural characteristics and
neuropsychological data demonstrated that, in Alzheimer’s disease (AD) patients, frontal lobe
symptoms were associated with more pronounced cognitive deficits (of frontal origin). Moreover,
frontal lobe symptoms were associated with increased severity and frequency of agitated and
aggressive behaviour, and with increased severity of psychosis and depressive symptoms. We
demonstrated that the evolution of frontal lobe symptoms in relation to dementia severity is
significantly different comparing AD and frontotemporal dementia (FTD) and dementia with Lewy
bodies (DLB) patient groups putting emphasis on behavioural observation as a tool to discriminate
between several forms of dementia (Aries et al., 2010).
To determine the reliability of the 30-item Geriatric Depression Scale (GDS-30) for the screening of
depressive symptoms in dementia and mild cognitive impairment (MCI), we set up a study using
the Cornell Scale for Depression in Dementia (CSDD) as the ‘gold standard’. Diagnosed according
to strictly applied clinical diagnostic criteria, patients with MCI (n=156) and probable Alzheimer’s
AD (n=247) were included. In MCI patients, moderate but highly significant correlations were
found between GDS-30 and CSDD scores. In mildly, moderately and severely affected AD patients,
only weak correlations between GDS-30 and CSDD scores were calculated. ROC curve analysis
showed that sensitivity and specificity values of respectively 95% and 67% were achieved when a
GDS-30 cut-off score of 8 was applied in MCI patients. In AD patients, too low sensitivity and
specificity values did not allow selecting an optimal cut-off score by means of ROC curve analysis.
Using the CSDD as ‘gold standard’, we demonstrated that the GDS-30 is a reliable screening tool
for depressive symptoms in MCI but not in AD patients (Debruyne et al., 2009).
Scientific Report Institute Born-Bunge 2010. Page 5
B. Biomarkers in cerebrospinal fluid
To establish diagnostic performance of the cerebrospinal fluid (CSF) biomarkers β-amyloid peptide
(Aβ1-42), total tau-protein (T-tau) and tau phosphorylated at threonine 181 (P-tau181P) compared
to clinical diagnosis, biomarker levels were determined in CSF samples from 100 autopsyconfirmed dementia and 100 control subjects (Engelborghs et al., 2008a). New biomarker-based
models were constructed by means of logistic regression. Using all biomarkers, dementia could be
discriminated from controls (sensitivity (S) = 86 %, specificity (Sp) =89 %). T-tau and Aβ1-42
optimally discriminated AD from other dementias (non-AD) and controls (S = 90 %, Sp = 89 %).
AD was optimally discriminated from non-AD using P-tau181P and Aβ1-42 (S = 80 %, Sp = 93
%). Diagnostic accuracy of the latter model (82.7 %) was comparable to clinical diagnostic
accuracy (81.6 %) that was based on a whole clinical work-up (including imaging). This study has
demonstrated the value of a combined assessment of CSF biomarkers in differential dementia
diagnosis, using pathological diagnosis as a reference. New biomarker-based models have been
developed, achieving sensitivity, specificity, and diagnostic accuracy levels, consistently exceeding
80 %. These findings meanwhile support the original hypothesis that the combined assessment of
the CSF biomarkers Aβ1-42, T-tau and P-tau181P reveal S, Sp and diagnostic accuracy levels that
are high enough to discriminate AD from other forms of dementia.
To establish diagnostic accuracy and optimal cut-off levels of CSF P-tau181P for discriminating
AD from non-AD dementias in autopsy-confirmed dementia patients, CSF levels of Aβ1-42, T-tau
and P-tau181P from patients with definite AD (n=95) and non-AD dementias (n=50) were
determined with single-parameter ELISA kits (Koopman et al., 2009). Optimal P-tau181P cut-off
levels for differentiating AD from pooled non-AD dementias, DLB and FTD were 50.4 pg/mL
(diagnostic accuracy: 73%), 52.8 pg/mL (diagnostic accuracy: 73%) and 35.3 pg/mL (diagnostic
accuracy: 90%) respectively. It was concluded that the optimal CSF P-tau181P cut-off level for
discriminating AD from non-AD dementias was 50.4 pg/mL. Optimal CSF P-tau181P cut-off levels
differed between non-AD diagnostic dementia categories.
To investigate whether CSF biomarkers could have helped the clinician in differential dementia
diagnosis in case of clinically ambiguous diagnoses, we set up a study using autopsy-confirmed
dementia diagnosis as gold standard (Le Bastard et al., 2010b). Twenty-two patients of our autopsyconfirmed dementia population totalling 157 patients had an ambiguous clinical diagnosis at CSF
sampling and were included in statistical analysis. CSF levels of Aβ1-42, T-tau and P-tau181P were
determined. A biomarker-based model was applied to discriminate between AD and non-AD
dementias. AD and non-AD patients showed no significant differences in Aβ1-42 and T-tau
concentrations, whereas P-tau181P concentrations were significantly higher in AD compared to
non-AD patients. The biomarker-based diagnostic model correctly classified 18 of 22 (82%)
patients with clinically ambiguous diagnoses. It was concluded that using a biomarker-based model
in patients with clinically ambiguous diagnoses, a correct diagnosis would have been established in
the majority of autopsy-confirmed AD and non-AD cases, indicating that biomarkers have an added
diagnostic value in cases with ambiguous clinical diagnoses.
The clinical diagnosis of AD is highly uncertain and error prone in the early stages of the disease.
We therefore sought to identify biomarker patterns typical for AD in an independent, unsupervised
way, without using information on the clinical diagnosis (De Meyer et al., 2010). Application of a
mixture modeling approach using CSF-derived Aβ1-42, total tau protein, and P-Tau181 protein as
biomarkers on a clinically well-characterized data set that included cognitively normal persons, AD
patients, and individuals with MCI. The outcome of the qualification analysis was validated on two
additional data sets, one of which was autopsy-confirmed. Using the US-ADNI data set, a CSFAβ1-42/ P-Tau181P biomarker mixture model identified one feature linked to AD, while the other
matched the ‘healthy’ status. The AD signature was found in 90%, 72%, and 36% of patients in the
AD, MCI, and cognitively normal groups, respectively. The cognitively normal group with the AD
Scientific Report Institute Born-Bunge 2010. Page 6
signature was enriched in apolipoprotein E e4 allele carriers. Results were validated on other data
sets. In one study consisting of 68 autopsy-confirmed AD cases, 64 of 68 patients (94% sensitivity)
were correctly classified with the AD feature. In another data set with MCI patients followed up for
5 years, the model showed a sensitivity of 100% (57/57) in patients progressing to AD. The mixture
modeling approach, totally independent of clinical AD diagnosis, accurately correctly classified AD
patients. The unexpected presence of the AD signature in more than one third of cognitively normal
subjects suggests that AD pathology is active and detectable earlier than has heretofore been
envisioned.
To identify neurochemical correlates of behavioural and psychological signs and symptoms of
dementia (BPSD), we set up a prospective study (Engelborghs et al., 2008b). CSF levels of
metabolites of (nor)epinephrine (MHPG), serotonin (5HIAA) and dopamine (DOPAC, HVA) were
determined by HPLC and electrochemical detection. Spearman Rank-Order followed by
Bonferroni correction was used for calculating correlations. In FTD patients, CSF norepinephrine
levels were positively correlated with dementia severity (r=0.539; p=0.021). CSF DOPAC levels
were correlated with BPSD in general (r=0.539; p=0.021), associated caregiver burden (r=0.567;
p=0.004) and agitated and aggressive behaviour (r=0.568; p=0.004). In a subgroup of FTD patients
who did not receive psychotropic pharmacological treatment, a strong correlation between CSF
HVA/5HIAA ratios (reflecting serotonergic modulation of dopaminergic neurotransmission) and
aggressive behaviour (r=0.758; p=0.009) was found. In MXD patients, (verbally) agitated behaviour
was positively associated with the turnover of norepinephrine (r=0.633; p=0.002). No significant
correlations were found in AD and DLB groups. In FTD, increased activity of dopaminergic
neurotransmission and altered serotonergic modulation of dopaminergic neurotransmission was
associated with agitated and aggressive behaviour respectively (Engelborghs et al., 2008b). This
study demonstrated that neurochemical mechanisms underlying the pathophysiology of BPSD are
both BPSD-specific and disease-specific which might have implications for future development of
new and more selective pharmacological treatments of BPSD.
C. Biomarkers in plasma
Plasma β-amyloid protein (Aβ) isoforms are considered potential biomarkers for AD and dementia.
We recently set up two pilot studies.
To evaluate the diagnostic performance of full-length and N-truncated plasma Aβ forms in patients
with AD and non-AD as compared to healthy control subjects, a pilot study was set up (Le Bastard
et al., 2010a). Plasma samples from 50 AD, 50 non-AD and 49 control subjects were included and
analysed using a multiparameter fluorimetric bead-based immunoassay for the simultaneous
quantification of different Aβ forms. No significant differences in Aβ isoforms were detected
between dementia and controls; or AD, non-AD and controls. Compared to control subjects, pooled
dementia patients (AD and non-AD) and AD patients alone had significantly lower plasma Aβ142/AβN-42 ratios. In each diagnostic group, all plasma Aβ concentrations were significantly
correlated. Except for the Aβ1-42/Aβ1-40 ratio in controls, no significant correlations between
plasma Aβ forms and age were found. In conclusion, low diagnostic performance of cross-sectional
plasma Aβ measurements hampers future application as diagnostic markers. The possible
application of longitudinal plasma Aβ measurements as screening tools for dementia remains to be
elucidated.
The relation between plasma and CSF levels of Aβ isoforms remains unclear. In order to identify
possible correlations between Aβ levels in plasma and CSF we determined Aβ levels in time-linked
plasma and CSF samples (Le Bastard et al., 2009). Aβ concentrations in plasma (Aβ1-42 and AβN42) and CSF (Aβ1-42) samples from 49 AD patients, 47 non-Alzheimer’s disease dementia (nonAD) patients, 39 MCI patients and 29 controls were determined using a multi-parameter
fluorimetric bead-based immunoassay using xMAP® technology (for plasma) and a conventional
single-parameter ELISA (for CSF). Plasma Aβ1-42 concentrations did not correlate with CSF Aβ142 concentrations in the total study population, or in the different diagnostic groups. No correlations
Scientific Report Institute Born-Bunge 2010. Page 7
between plasma AβN-42 and CSF Aβ1-42 levels were found either. The CSF/serum albumin index
did not show any significant differences between AD, non-AD, MCI and controls. These results
suggest that the Aβ levels in plasma are independent of the Aβ levels in CSF both in dementia and
controls. The fact that CSF and plasma Aβ do not correlate in patients as well as controls and no
significant differences in plasma Aβ1-42 or AβN-42 between patients and controls can be detected,
might hamper the diagnostic utility of the plasma Aβ levels as diagnostic markers for dementia.
We investigated whether blood N-glycan changes can be used as a diagnostic biomarker for AD
(Chen et al., 2010). We used DNA sequencer-assisted, fluorophore-assisted carbohydrate
electrophoresis (DSA-FACE) technology to assay N-glycans in sera from 79 autopsy-confirmed
dementia patients and 149 healthy controls. One N-glycan (NA2F) was substantially decreased in
AD patients but not in controls. Use of NA2F for discriminating AD between dementia patients and
healthy controls showed a diagnostic accuracy of 85.7% +/- 2.8% with 92% specificity and 70%
sensitivity. The decrease in the level of NA2F in AD patients compared to non-AD patients was
more pronounced in females (p < 0.0001) than in males (p < 0.014). Use of NA2F to differentiate
female AD from female non-AD patients reached a diagnostic accuracy of 90.7% +/- 4.8 %.
Pearson correlation analysis showed that in female dementia patients, serum NA2F levels were
significantly correlated with the CSF Aβ1-42 and P-tau181P levels, whereas in male dementia
patients serum NA2F levels were significantly correlated only with CSF total tau protein (T-tau)
level. Thus, we suggest that the serum N-glycan marker might be suitable for longitudinal and
follow-up studies.
D. Behavioural Neurology / Behavioural Psychology
By means of case histories, neuropsychological and neurolinguistic aspects of language and
behaviour in various syndromes were studied (Baillieux et al., 2008a, 2008b, 2009, 2010; De Smet
et al., 2009; De Witte et al., 2008a, 2008b; Mariën et al., 2008, 2009a, 2009b, 2010; Vandervliet et
al., 2008). In addition, a DLB patient with olanzapine-induced head drop was described (Aries et
al., 2008).
With regard to AD, several new hypotheses were formulated that will be subjected to prospectively
controlled clinical studies in the near future (Wostyn et al., 2008a, 2008b, 2009a, 2009b, 2009c,
2010a, and 2010b). In addition, we set up a study to investigate whether neuropsychological tests
are able to predict conversion to AD among MCI patients. At baseline the cognitive part of the
Cambridge Examination for Mental Disorders of the Elderly (CAMCOG), the Mini Mental Status
Examination (MMSE), the Geriatric Depression Scale (GDS), a Dutch variation of Rey's Auditory
Verbal Learning Test, the Memory Impairment Screen plus (MISplus) and the Visual Association
Test (VAT) were administered to 40 patients diagnosed with MCI. After 18 months, MCI-patients
were reassessed and a follow-up diagnosis was established. This prospective, longitudinal study
shows that a score of 0 or 1 out of 6 on the MISplus may be a good indicator of future (within 18
months) progression to AD among MCI-patients (Dierckx et al., 2009).
E. Study of Cerebrovascular Disease
Actigrafic recording was validated as an objective instrument to assess stroke-related motor deficits
(Gebruers et al., 2008). In addition, clinimetric properties and clinical applicability of different
accelerometry-based measurement techniques in persons with stroke were review (Gebruers et al.,
2010).
Within the framework of the Middelheim Interdisciplinary Stroke Study (MISS) relevant results
regarding clinical, biochemical and imaging parameters were generated. In a review concerning the
ischemic cascade a detailed description of important processes in the acute phase of stroke was
given (Brouns et al., 2009a).
Scientific Report Institute Born-Bunge 2010. Page 8
Improved insight in the role of neurotransmitters in acute cerebral ischemic injury may be
fundamental for the successful development of novel therapeutic approaches. We investigated
excitatory amino acids and monoaminergic neurotransmitters in CSF of acute ischemic stroke
patients and their relation to stroke characteristics, i.e., stroke severity (NIHSS score at admission,
lesion volume), stroke evolution in the subacute phase, long-term stroke outcome, lesion location,
and stroke etiology. Neurotransmitter systems display relevant interrelations, however, no
significant associations between neurotransmitter concentrations in CSF and stroke characteristics
were found, with the exception of higher 5-hydroxyindoleacetic acid levels in CSF of patients with
progressing stroke and poor long-term outcome (Brouns et al., 2010c).
Both from clinical and research standpoints, it may be highly relevant to differentiate between
small-artery and large-artery infarction in the acute phase of ischemic stroke. Diagnosis of acute
lacunar infarction can reliably be made, based on the conjunctive use of clinical evaluation and
measurement of D-dimer levels either by a standard assay or by a bedside testing kit (Brouns et al.,
2009e).
We studied the role of oxidative stress in acute ischemic stroke and hypothesised that asymmetric
and symmetric dimethylarginine (ADMA, SDMA) are released in CSF due to ischemia-induced
proteolysis and that CSF dimethylarginines are related to stroke severity. Logistic regression
analysis confirmed that dimethylarginines were independently associated with stroke severity. CSF
dimethylarginine levels are increased in hyperacute ischemic stroke and are associated with stroke
severity (Brouns et al., 2009c). We investigated the kinetics of serum uric acid concentrations in the
acute, subacute and chronic phase of ischemic stroke and its relation with initial stroke severity,
stroke evolution in the subacute phase and long-term stroke outcome, and observed that decreases
in uric acid during the first week after onset of stroke correlates with more severe stroke,
unfavorable stroke evolution, and poor long-term stroke outcome (Brouns et al., 2010f). These
observations indicate that prolonged oxidatve stress is an important source of secondary damage
following cerebral ischemia.
Reproducibility and clinical relevance of quantitative EEG parameters in cerebral ischemia were
assessed (Sheorajpanday et al., 2009).
We investigated the predictive value of standard neurological evaluation, a commercially available
biomarker assay and neuroimaging in the subacute phase for outcome after thrombolytic therapy in
ischemic stroke. Routine clinical evaluation, bedside testing of biochemical markers by the Triage
Stroke Panel and infarct volumetry on neuroimaging at 72 h after thrombolytic therapy are
predictors for long-term outcome of ischemic stroke patients. Clinical assessment is the most
reliable parameter for outcome prediction, but its predictive value is substantially improved when
combined with the biomarker panel (Brouns et al., 2009d).
Within the MISS project, we also focussed on the crucial role of hemostatic activation in acute
ischemic stroke. We indicated the clinical relevance of the procarboxypeptidase U /
carboxypeptidase U system in the treatment of acute ischemic stroke (Brouns et al., 2009b), as well
as in the spontaneous evolution of stroke (Brouns et al., 2010b).
Post-stroke inflammation may induce upregulation of the kynurenine pathway for tryptophan
oxidation, resulting in neuroprotective and neurotoxic metabolites. The activity of the kynurenine
pathway for tryptophan degradation in acute ischemic stroke correlates with stroke severity and
long-term stroke outcome. Tryptophan oxidation is related to the stroke-induced inflammatory
response (Brouns et al., 2010d.)
Accumulation of lactate in ischemic regions has been documented in acute stroke. We evaluated the
relation between lactate levels in blood and CSF and ischemic stroke evolution and outcome.
Lactate was measured in blood of 187 acute ischemic stroke and TIA patients at admission, 24 h, 72
h and 7 days after stroke onset. In a subpopulation of 85 stroke patients and in 51 controls, lactate
was measured in CSF. Lactate levels in CSF, but not in blood, are a reliable marker for metabolic
Scientific Report Institute Born-Bunge 2010. Page 9
crisis in acute ischemic stroke and correlate with the stroke evolution in the subacute phase and with
long-term outcome (Brouns et al., 2008).
Ischemic injury to the central nervous system causes cellular activation and disintegration, leading
to release of cell-type-specific proteins into the CSF. We investigated CSF concentrations of myelin
basic protein (MBP), glial fibrillary astrocytic protein (GFAP), the calcium-binding protein S100B,
and neuron-specific enolase (NSE) in acute ischemic stroke patients and their relation to initial
stroke severity, stroke location, and long-term stroke outcome. We observed that MBP, GFAP,
S100B, and NSE display relevant differences in cellular and subcellular origins, which are reflected
in their relation to stroke characteristics. MBP is a marker for infarct location. GFAP and S100B
correlate with stroke severity and outcome (Brouns et al., 2010a).
Data on the prevalence of Fabry disease in patients with central nervous system pathology are
limited and controversial. In this study, we assessed the prevalence of Fabry disease in young
patients presenting with cerebrovascular disease in Belgium. In a national, prospective, multicenter
study, we screened for Fabry disease in 1000 patients presenting with ischemic stroke, transient
ischemic attack, or intracranial hemorrhage; unexplained white matter lesions; or vertebrobasilar
dolichoectasia. In male patients, we measured alpha-galactosidase A (alpha-GAL A) activity in
dried blood spots. Female patients were screened for mutations by exonic DNA sequencing of the
alpha-GAL A gene. Alpha-GAL A deficiency may play a role in up to 1% of young patients
presenting with cerebrovascular disease. These findings suggest that atypical variants of Fabry
disease with late-onset cerebrovascular disease exist, although the clinical relevance is unclear in all
cases (Brouns et al., 2010e).
The Belgian Stroke Council prepared a consensus document providing a set of minimum criteria to
meet international standards for stroke care. It is intended to provide help in the creation of stroke
units in centers who do not currently have one and to provide a benchmark for centres already
having organised stroke care (Thijs et al., 2009). The risk factors for depression after stroke were
reviewed (De Ryck et al., 2009).
Employing biochemical parameters, we proofed that the extent of blood brain barrier failure after
acute ischemic stroke correlates with stroke severity, evolution and clinical outcome (Brouns et al.
revision submitted in Eur. Neurol.).
II.2 From the IBB Biobank and the Laboratory of Ultrastructural Neuropathology (C. Ceuterick,
J-J. Martin and co-workers)
A. Neurodegenerative disorders
The diagnosis of a series of conditions characterized by dementia depends from the
neuropathological and immunohistochemical study of representative areas of the central nervous
system. The accurate description of the structure and of the topography of the histological lesions is
a prerequisite for further research. As a result of this morphological approach and taking into
account the recommendations of international collaborative groups it is possible to give a correct
neuropathological diagnosis of a series of neurodegenerative disorders affecting the nervous system.
These results are then used as a golden standard for research in the field of neurochemistry and
molecular genetics. Conversely the results of this research can be used to improve the
histopathological classification of the disorders, eg in the field of the fronto-temporal lobe
dementias (FTLD).
The brains of patients who have been adequately examined during their life are removed within 2-3
hours after death. The right half of the brain, brainstem and cerebellum is fixed in formalin, while
the left part of the brain is immediately deep-frozen. After a period of 2-4 weeks, the formalin-fixed
Scientific Report Institute Born-Bunge 2010. Page 10
part of the brain is photographed and examined macroscopically. Representative parts of the brain
(Brodmann’s areas 6, 7, 8, 9, 10, 11, 12, 17, 18, 22, 24, 46, neostriatum, putamen and pallidum,
thalamus at the level of the centrum medianum, corpus subthalamicum, mesencephalon, pons at the
level of the locus coeruleus, medulla oblongata and cerebellum) are embedded in paraffin. Classical
staining techniques like cresyl violet and HE are used for the cytology, the method of Gallyas for
the neurofibrillary tangles, the method of Klüver-Barrera for the myelin. Immunohistochemistry is
made with antibodies against hyperphosphorylated tau (AT8), amyloid Aß+ (4G8), ubiquitine,
alpha-synucleïne and against glial fibrillary acidic protein according to standard methods.
The subsequent table summarizes the results obtained from Jan, 2008 to December 2010.
Neuropathological diagnosis
Senile dementia Alzheimer type (SDAT)
Mixed dementia (vascular +SDAT)
Lewy body disease (various forms)
FTLD
Progressive supranuclear palsy
Huntington’ chorea
Multiple system atrophy
Parkinson’s disease
Amyotrophic lateral sclerosis
Creutzfeldt-Jakob disease
Nasu-Hakola disease
Control cases and other neurological disorders
2008
19
3
2
5
1
2
0
5
2
6
0
17
Number of cases
2009
29
5
2
2
2
4
1
1
0
10
0
78
2010
23
4
6
1
4
1
5
4
1
16
1
33
The Laboratory of Ultrastructural Neuropathology, affiliated with the IBB Biobank provided over
the years 2008 - 2010 well documented tissue samples, qualified technical support and expertise.
The research activities of LUN and Taskforce f1 concerned:
Scientific work and participation in interdisciplinary (Tf1 and Tf3 Biobank) scientific research
projects and publications.
With regards to neurodegenerative, the following studies were established:
- Requiring ultrastructural expertise for the structural identification and description of inclusion
bodies in dementias (Wils et al, 2010) and neurometabolic storage disorders (Boustany et al. –
bookchapter, Feb 2011).
- We have contributed to a BEFAS project (principal investigator: Prof. Dr. P. P. De Deyn)
examining skin biopsies by EM of patients suspected of Fabry disease. Our skin biopsy findings
have been added in a paper concerning a patient with Fabry disease and Turner syndrome (Brouns
et al, in press).
B. Genetic, inflammatory and metabolic myopathies
Study of the mutations of the ryanodine receptor may cause dominant and recessive forms of
congenital myopathies with cores. The investigation of 9 families presenting with a recessive form
of the disease has allowed the identification of a mutation of both alleles of the RYR1 gene for all
patients. We demonstrated that the recessive core myopathies were caused by the presence of one
recessive null allele and that the variability of the phenotype depended on the nature of the mutation
present on the second allele (Monnier et al. 2008).
We reported the clinical and genetical characteristics of a young female patient with exertional
muscle pain as the only presenting symptom of dystrophinopathy and of her family (Ceulemans et
al. 2008).
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The characteristics of different chaperone proteins was analyzed in inflammatory myopathies (de
Paepe et al. 2009a). Our results point to a general protective role for both HSP90 and HSP70
families in damaged muscle fibres and a specific cytotoxic role for HSP90 in muscle fibre invasion
associated with inclusion body myositis and polymyositis.
We have shown that the immunohistochemical detection of OXPHOS complexes could be a
valuable additional diagnostic tool for the evaluation of mitochondrial cytopathy (de Paepe et al.
2009b).
Liver biopsies with COX staining could yield crucial data concerning mitochondrial myopathies.
Mitochondrial mosaics are probably more frequent than initially thought (Roels et al. 2009).
Findings suggestive of a defect in biosynthesis of the mitochondrially encoded subunits of the
OXPHOS complexes were discovered in a case of lactic acidosis in a newborn with adrenal
calcifications (Zecic et al. 2009).
DNAJB2 a co-chaperone regulator of Hsp 70 that is expressed principally in the nervous system, is
also expressed in mouse and human skeletal muscle at the neuromuscular junction of normal fibres,
in the cytoplasm and membrane of regenerating fibres and in protein aggregates and vacuoles in
protein aggregate myopathies. We propose a role for DNAJB2 protein turnover processes in skeletal
muscle (Claeys et al., 2010).
C. Inherited peripheral neuropathies
Our histopathological results regarding more remarkably the absence of minifascicle formation in a
sural nerve biopsy of a patient with a XY gonadal dysgenesis and peripheral neuropathy,
contributed to the expansion of the clinical and genetic heterogeneity in this entity (Baets et al.
2009).
We have contributed to the ultrastructural analysis of axonal ribosomes in inherited peripheral
neuropathies. Increases of axonal ribosomes were noted in CMT1 and CMT2. This observation can
be used as a diagnostic marker for diverse human nerve diseases (Verheijen et al, in press).
We have reported a patient with a GAN suggested by EM of a skin biopsy, due to a compound
heterozygosity for a maternally inherited microdeletion and a paternally inherited point mutation
(Buysse et al, 2010).
D. Routine histopathology including electron microscopy (EM) of tissues for diagnostic
purposes in a wide variety of neurological disorders
Over the years 2008 – 2010, Tf1 and LUN have had the opportunity to perform the following
histopathological studies:
-
210 LM analyses of skeletal muscles and peripheral nerves, using histology, histochemistry
and histo-enzymology (see table 1).
-
415 EM analyses of resin embedded samples using a CM10 FEI transmission electron
microscope (see tables 1 - 4).
-
79 Immunohistochemical studies of skeletal muscle and peripheral nerve: using a large
panel of antibodies against resp. membranous-, cytoskeletal-, myelin- and axonal proteins
and inflammatory parameters (see table 1).
Biopsies from patients for which no diagnosis had yet been available were reconsidered in attempt
to make a precise diagnosis or to get more insight in the disease process. Biopsies from affected
patients were reviewed for family members in the context of genetic counselling. Biopsies were
retrieved for genotype-phenotype correlation of identified molecular genetic analyses in hereditary
peripheral neuropathies. EM analyses/ research have been performed for centers without EM
facilities/ expertise. Assistance, support and advice have been given to neuropathologists and
researchers regarding a “second opinion” in complex diagnostical and technical work-ups.
Scientific Report Institute Born-Bunge 2010. Page 12
Neuromuscular biopsies
EM has been used within the histopathological work-up incl. light
microscopy (LM) of skeletal muscle disorders and peripheral neuropathies (table 1). EM has been
particularly useful for the diagnosis of some congenital myopathies (such as nemaline myopathy),
glycogenoses (type II, V/ VI) mitochondrial myopathies and “inclusion body myositis”. Most
biopsies were investigated for Centers of Reference for Neuromuscular Disorders and neurological
departments. In collaboration with Prof. Dr. L. Heytens, we have examined muscle biopsies from
numerous patients with a susceptibility to malignant hyperthermia (table 5). All investigated
samples have been stored and continuously included within the database of the IBB Biobank,
providing further research and exchanging facilities.
Table 1: Histopathological analyses: skeletal muscle and peripheral nerve
Year
2008
- LM
- EM
- Immuno
2009
- LM
- EM
- Immuno
2010
- LM
- EM
- Immuno
Muscles
Peripheral nerves
TOTAL
77
73
23
3
5
80
78
23
74
76
26
3
3
77
79
26
59
73
30
1
1
1
60
74
30
Skin and conjunctival biopsies from children with a progessive encephalopathy and adult patients
are still forwarded to LUN for its longstanding diagnostic expertise (table 2). This EM activity is a
scientific service to third parties. Patients with problematical diagnostical work-ups and helpful
clinical data are than selected. A neurometabolic storage disorder could be achieved (table 5) or
ruled out. Our findings were of great help to orientate molecular genetic studies. We have also
offered such diagnostic possibilities in CADASIL and in giant axonal neuropathy (GAN).
Table 2: EM of skin, conjunctiva and other tissues (chorion cells, liver, cellcultures)
Year
2008
2009
2010
Skin
65
62
69
Conjunctiva
3
Other
7
1
TOTAL
72
66
69
Brain biopsies/ autopsies were examined in rare neurological diseases (table 3). EM has been used
to complete morphological data from LM and immunohistochemistry.
Table 3: EM of human brain samples
Year
2008
2009
2010
Biopsies
0
2
1
Autopsies
1
2
1
Total
1
4
2
Scientific Report Institute Born-Bunge 2010. Page 13
Mouse material (table 4) has also been investigated for research purposes (in collaboration with
Prof. Dr. V. Timmerman).
Table 4: EM of mouse material
2009
2010
brain
1
0
spinal cord
1
0
peripheral nerve
0
6
Table 5: Histopathological diagnosis
Muscular diseases
Muscular dystrophies
Congenital myopathies
Metabolic myopathies
Inflammatory myopathies
Number of patients
11
8
17
18
In vitro test malignant hyperthermia
(Prof. Dr. L. Heytens)
Number of patients: 39
Positive tests
Peripheral neuropathies
Hereditary PNP
Acquired PNP
Number of patients
1 (?)
4
Neurometabolic disorders
Lysosomal disorders
Peroxisomal diseases
Other (GAN, CADASIL)
Number of patients
10
1
2
21
II.3 From Neurogenetics, Neurodegenerative Brain Diseases (C. Van Broeckhoven, M. Cruts and
co-workers)
Over the years, the Laboratory of Neurogenetics has contributed to the identification of causal
genes (positional cloning) and genetic predisposition (genetic association) for Alzheimer disease
(AD). In the Laboratory of Neurogenetics researchers are active in the field of Neurodegenerative
Brain diseases, Peripheral Neuropathies and Neurogenetics.
A. Alzheimer’s Disease
Replication of genetic association findings in independent studies represents an important validation
tool in the search for susceptibility genes for complex diseases such as AD. In a well-characterized
memory-clinic based study comprising 1078 unrelated AD patients and 652 control individuals, we
set out to replicate previously reported genome-wide association of four novel risk SNPs with AD
and onset age, with first stage p-values ranging from 0.001 to 0.000004. We obtained evidence for
association between rs179943, an intronic SNP in ATXN1 at 6p22.3, and affection status (OR =
0.63 (95% CI = 0.44-0.90; nominal p = 0.01)). Overall, our data provided independent support for
association of at least one chromosomal locus with AD and warranted a more in-depth investigation
of these regions for possible underlying functional variants (Bettens et al., 2010a).
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Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1
gene (CALHM1) is associated with the risk of developing AD. However, we could not replicate this
finding in our Belgian study population. In order to independently assess the association, we took
part in a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of
24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results
underscore our earlier findings that the CALHM1 P86L polymorphism is likely not a genetic
determinant of AD but may modulate age of onset by interacting with the effect of the ε4 allele of
the APOE gene (Lambert et al, 2010).
In two invited reviews the recent findings in the field of genetic of AD (identification of the new
risk genes CLU, CR1 and PICALM) are placed in a broader context. Suggestions as how to these
and future findings can be further explored and translated to the patient, are provided (Sleegers et al,
2010c; Bettens et al, 2010b).
Both leukocyte telomere length and the apolipoprotein epsilon4 allele have been associated with
mortality, cardiovascular disease, cognition, and dementia. We investigated whether leukocyte
telomere length was associated with APOE genotype or cognitive abilities in the context of APOE
genotype. The setting for this cross-sectional study was 427 non-demented individuals aged 41-81
years. We found that epsilon4 carriers overall exhibited significantly longer telomeres compared
with non-carriers (difference of 268 bp, p = 0.001). This difference was greatest at the lower limit
of the age span and non-significant at the upper limit, which translated into a significantly higher
telomere attrition rate (p = 0.049) among epsilon4 carriers (37 bp/years) compared with non-carriers
(21 bp/year). Further, longer telomeres among epsilon4 carriers significantly predicted worse
performance on episodic memory tasks. No significant associations were found on tasks tapping
semantic and visuospatial ability, or among epsilon3/epsilon3 carriers. In conclusion, APOE
epsilon4 carriers had longer telomeres compared with non-carriers, but higher rate of attrition.
Among them, longer telomeres predicted worse performance on episodic memory tasks. These
observations suggest that the epsilon4 allele is associated with abnormal cell turnover of functional
and possibly clinical significance (Wikgren et al, 2010).
The nuclear transactive response (TAR) DNA binding protein-43, TDP-43, is a major constituent of
the ubiquitinated neuronal inclusions in patients with frontotemporal lobar degeneration (FTLD)
and amyotrophic lateral sclerosis (ALS). Missense mutations in TDP-43 have been associated with
familial and sporadic ALS. Since TDP-43 immunoreactivity was also frequently observed in
Alzheimer's disease (AD) brains and elevated TDP-43 plasma levels were detected in a subset of
AD patients, we sequenced the TDP-43 gene, TARDBP, in a well-documented group of AD
patients (n=485). We observed one mutation in exon 3 (c.269C>T) predicting a p.Ala90Val
substitution in two patients. One extra p.Ala90Val carrier was observed by sequencing exon 3 of an
additional set of 254 AD patients. The mutation was absent from 604 control individuals. Allele and
haplotype analysis using microsatellite markers suggested that the three patients might share a
common founder. However, co-segregation of p.Ala90Val with AD could not be realized leaving its
pathogenic unclear at this moment. Also, sequencing in 190 additional AD patients of TARDBP
exon 6 in which pathogenic mutations have been reported in FTLD and ALS was negative. Further,
genetic association analyses using five single nucleotide polymorphisms did not detect significant
differences between AD patients and control individuals. In conclusion, the genetic contribution of
TARDBP to AD was restricted to the rare mutation p.Ala90Val (3/739, 0.4%) of unclear pathogenic
nature that affects the nuclear localization signal in TDP-43 (Brouwers et al., 2010).
Serum or plasma progranulin (GRN) is a highly accurate of GRN-related frontotemporal lobar
degeneration, which is caused by loss-of-function mutations in the GRN gene. Both null mutations
and missense mutations in GRN have also been observed in patients with AD. Here, the evidence
for a role of circulating GRN as a biochemical biomarker in neurodegeneration is reviewed, with a
specific focus on its relevance in AD. We conclude that circulating GRN is a promising,
nonintrusive biomarker that warrants screening in both patients with dementia of the Alzheimer
Scientific Report Institute Born-Bunge 2010. Page 15
type and people with mild cognitive impairment; specifically for, but not limited to, those that have
a positive family history of neurodegenerative disease. Once a cure for GRN-related
neurodegeneration becomes available, this biomarker will be an important tool in the effort to
personalize treatment of dementia (Sleegers et al., 2010a).
B. Frontotemporal Lobe Dementia and Tauopathies
Neuronal cytoplasmic and intranuclear aggregates of RNA-binding protein TDP-43 are a hallmark
feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and
frontotemporal lobar degeneration (FTLD). ALS and FTLD show a considerable clinical and
pathological overlap and occur as both familial and sporadic forms. Though missense mutations in
TDP-43 cause rare forms of familial ALS, it is not yet known whether this is due to loss of TDP-43
function or gain of aberrant function. Moreover, the role of wild-type (WT) TDP-43, associated
with the majority of familial and sporadic ALS/FTLD patients, is also currently unknown.
Generating homozygous and hemizygous WT human TDP-43 transgenic mouse lines, we show
here a dose-dependent degeneration of cortical and spinal motor neurons and development of
spastic quadriplegia reminiscent of ALS. A dose-dependent degeneration of nonmotor cortical and
subcortical neurons characteristic of FTLD was also observed. Neurons in the affected spinal cord
and brain regions showed accumulation of TDP-43 nuclear and cytoplasmic aggregates that were
both ubiquitinated and phosphorylated as observed in ALS/FTLD patients. Moreover, the
characteristic approximately 25-kDa C-terminal fragments (CTFs) were also recovered from
nuclear fractions and correlated with disease development and progression in WT TDP-43 mice.
These findings suggest that approximately 25-kDa TDP-43 CTFs are noxious to neurons by a gain
of aberrant nuclear function (Wils et al., 2010).
Null mutations in progranulin (GRN) are associated with frontotemporal lobar degeneration
characterized by intraneuronal accumulation of TAR DNA-binding protein-43 (TDP-43). However,
the mechanism by which GRN-deficiency leads to neurodegeneration remains largely unknown. In
primary cortical neurons derived from Grn knockout (Grn(-/-)) mice, we found that Grn-deficiency
causes significantly reduced neuronal survival and increased caspase-mediated apoptosis, which
was not observed in primary mouse embryonic fibroblasts (MEFs) derived from Grn(-/-) mice.
Also, neurons derived from Grn(-/-) mice showed an increased amount of phosphorylated TDP-43
accumulations. Furthermore, proteasomal inhibition with MG132 caused increased caspasemediated TDP-43 fragmentation and accumulation of detergent-insoluble 35- and 25-kDa Cterminal fragments (CTFs) in Grn(-/-) neurons and MEFs. Interestingly, full-length TDP-43 also
accumulated in the detergent-insoluble fraction, and caspase-inhibition prevented MG132-induced
generation of TDP-43 CTFs but did not block the pathological conversion of full-length TDP-43
from soluble to insoluble species. These data suggest that GRN functions as a survival factor for
cortical neurons and GRN-deficiency causes increased susceptibility to cellular stress. This leads to
increased aggregation and accumulation of full-length TDP-43 along with its C-terminal derivatives
by both caspase-dependent and independent mechanisms (Kleinberger et al., in press).
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative condition that predominantly
affects behavior, social awareness, and language. It is characterized by extensive heterogeneity at
the clinical, pathological, and genetic levels. Recognition of these levels of heterogeneity is
important for proper disease management. The identification of progranulin and TDP-43 as key
proteins in a significant proportion of FTLD patients has provided the impetus for a wealth of
studies probing their role in neurodegeneration. This review highlights the most recent
developments and future directions in this field and puts them in perspective of the novel insights
into the neurodegenerative process, which have been gained from related disorders, e.g., the role of
FUS in amyotrophic lateral sclerosis (Sleegers et al., 2010b).
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The FUS gene was identified as a new causal gene for ALS in approximately 4% of patients with
familial ALS. Since ALS and FTLD are part of a clinical, pathologic, and genetic disease spectrum,
we investigated a potential role of FUS in FTLD. We performed mutational analysis of FUS in 122
patients with FTLD and 15 patients with FTLD-ALS, as well as in 47 patients with ALS. Mutation
screening was performed by sequencing of PCR amplicons of the 15 FUS exons. We identified 1
patient with FTLD with a novel missense mutation, M254V, that was absent in 638 control
individuals. In silico analysis predicted this amino acid substitution to be pathogenic. The patient
did not have a proven family history of neurodegenerative brain disease. Further, we observed the
known R521H mutation in 1 patient with ALS. No FUS mutations were detected in the patients
with FTLD-ALS. While insertions/deletions of 2 glycines (G) were suggested to be pathogenic in
the initial FUS reports, we observed an identical GG-deletion in 2 healthy individuals and similar
G-insertions/deletions in 4 other control individuals, suggesting that G-insertions/deletions within
this G-rich region may be tolerated. In a first analysis of FUS in patients with FTLD, we identified
a novel FUS missense mutation, M254V, in 1 patient with pure FTLD. At this point, the biologic
relevance of this mutation remains elusive. Screening of additional FTLD patient cohorts will be
needed to further elucidate the contribution of FUS mutations to FTLD pathogenesis (Van
Langenhove et al., 2010).
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are overlapping
neurodegenerative disorders. Mutations in the growth factor progranulin (PGRN) gene cause FTLD,
sometimes in conjunction with ALS; such mutations are also observed in some ALS patients. Most
PGRN mutations underlying FTLD are null mutations that result in reduced PGRN levels. We
investigated PGRN expression in human ALS and in mouse models of motor neuron degeneration.
Progranulin plasma or CSF levels in newly diagnosed ALS patients did not differ from those in
healthy or disease controls (PGRN mutation-negative FTLD and Alzheimer disease patients). In the
mutant SOD1 mouse model of ALS, spinal cord PGRN levels were normal in presymptomatic
animals but increased during the degenerative process. This increase in PGRN correlated with
enhanced expression of PGRN in microglia. In CSF, PGRN levels were normal in presymptomatic
and early symptomatic animals, but with disease progression, a raise in PGRN was detectable.
These data indicate that upregulation of PGRN is a marker of the microglial response that occurs
with progression in motor neuron diseases (Philips et al, 2010).
Excitotoxicity is thought to play a pathogenic role in amyotrophic lateral sclerosis (ALS).
Excitotoxic motor neuron death is mediated through the Ca(2+)-permeable alpha-amino-3-hydroxy5-methyl-4-isoxazole propionic acid (AMPA)-type of glutamate receptors and Ca(2+) permeability
is determined by the GluR2 subunit. We investigated whether polymorphisms or mutations in the
GluR2 gene (GRIA2) predispose patients to ALS. Upon sequencing 24 patients and 24 controls no
non-synonymous coding variants were observed but 24 polymorphisms were identified, 9 of which
were novel. In a screening set of 310 Belgian ALS cases and 794 healthy controls and a replication
set of 3157 cases and 5397 controls from 6 additional populations no association with susceptibility,
age at onset, or disease duration was observed. We conclude that polymorphisms in the GluR2 gene
(GRIA2) are not a major contributory factor in the pathogenesis of ALS (Bogaert et al, 2010).
C. Parkinson’s disease
Lewy body diseases (LBD) are a group of clinically and pathologically overlapping brain disorders
characterized by specific brain lesions named Lewy bodies (LB). Parkinson disease marks one end
(extrapyramidal) of the spectrum while the LB variant of AD marks the other (cognitive). We
hypothesize that studying the genetic etiology of different members of the spectrum may eventually
elucidate the links between them and the underlying mechanism involved.
Parkinson disease is the second most commen neurodegenerative disorder. Five familial PD genes
and many more loci have been identified during the last decade. The relative contribution of simple
mutations and copy number variations (CNVs) in the 5 familial genes (SNCA, PARK2, PINK1,
Scientific Report Institute Born-Bunge 2010. Page 17
PARK7, and LRRK2) to the genetic etiology of Parkinson disease (PD) is still unclear because
most studies did not completely analyze each gene. To date, molecular genetic analyses have
identified over 500 distinct DNA variants in five disease genes associated with familial Parkinson
disease; α-synuclein (SNCA), parkin (PARK2), PTEN-induced putative kinase 1 (PINK1), DJ-1
(PARK7), Leucine-rich repeat kinase 2 (LRRK2). These genetic variants include ~82% simple
mutations and ~18% copy number variations. Some mutation subtypes are likely underestimated
since only few studies reported extensive mutation analyses of all five genes, by both exonic
sequencing and dosage analyses. We generated an update of all mutations published to date in the
literature, systematically organized in a novel mutation database
(http://www.molgen.ua.ac.be/PDmutDB). In addition, we addressed the biological relevance of
putative pathogenic mutations. This study emphasizes the need for comprehensive genetic screening
of Parkinson patients followed by an insightful study of the functional relevance of observed
genetic variants. Moreover, while capturing existing data from the literature it became apparent that
several of the five Parkinson genes were also contributing to the genetic etiology of other Lewy
Body Diseases and Parkinson-plus syndromes, indicating that mutation screening is recommendable
in these patient groups (Nuytemans et al., 2010).
In addition to the 5 familial PD genes we screen for mutations in newly reported functionally
relevant NBD genes in order to estimate their contribution to the genetic etiology of PD in the
Belgian patient group. In 2008 missense mutations were identified in the Grb10-Interacting GYF
Protein-2 gene (GIGYF2), located in the chromosomal region 2q36-q37, in familial Parkinson
disease (PD) patients of European descent. To determine the contribution of GIGYF2 mutations in
an extended (N=305) Belgian series of both familial and sporadic PD patients, we sequenced all 32
coding and non-coding exons of GIGYF2. In three sporadic PD patients we identified two novel
heterozygous missense mutations (c.1907A>G, p.Tyr636Cys and c.2501G>A, p.Arg834Gln), that
were absent from control individuals (N=360). However, since we lack genetic as well as functional
data supporting their pathogenic nature, we cannot exclude that these variants are benign
polymorphisms. Together, our results do not support a role for GIGYF2 in the genetic etiology of
Belgian PD (Meeus et al., 2011).
High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2
gene in Parkinson’s disease (PD) susceptibility. Therefore, we performed a large-scale analysis of
the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson’s disease
(GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status,
gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of
PD (patients). Genotyping was performed for the five most informative SNPs spanning the
Omi/HtrA2 gene in approximately 2–3 kb intervals (rs10779958, rs2231250, rs72470544,
rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk
estimates of Omi/HtrA2 variants. The 20 GEO-PD sites provided data for 6378 cases and 8880
controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed
using either fixed effect or random effect models. The summary odds ratios ranged between 0.98
and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q
statistics for all 5 SNPs; I2 estimates 0–8%). This largest association study performed to define the
role of any gene in the pathogenesis of Parkinson’s disease revealed no overall strong association of
Omi/HtrA2 variants with PD in populations worldwide (Krüger et al., 2010).
We attempted to identify the genetic defect underlying juvenile parkinsonism and dementia in a
patient of Afghan origin, who was born to consanguineous parents using direct sequencing of
known PD genes. The index patient developed tremor, right-sided dystonia and bradykinesia at age
10. Rapid cognitive decline resulted in dementia at age 13. A homozygous 2 bp deletion was
detected in exon 23 of the ATP13A2 gene in the index patient. We can conclude that the resulting
frameshift mutation is most likely responsible for truncation and loss of function of the ATP13A2
Scientific Report Institute Born-Bunge 2010. Page 18
protein. The clinical features of the index patient are consistent with Kufor-Rakeb syndrome (KRS),
a rare juvenile parkinsonian disorder with pyramidal signs, supranuclear gaze palsy and dementia.
The role of heterozygous mutations in ATP13A2 remains elusive, as shown by the variable
penetrance of the mutation in this family. This novel mutation in ATP13A2 further extends the
clinical and genetic spectrum of KRS. Further functional studies need to address the effect of this
mutation on transcript and protein level (Crosiers et al., 2010).
Dementia with Lewy bodies (DLB) is a central player in the LBD spectrum and the second most
frequent form of neurodegenerative dementia after AD. Since informative DLB families are scarce,
little is presently known about the molecular genetic etiology of DLB. We recently mapped the first
locus for DLB on chromosome 2q35-q36 in a multiplex Belgian family, DR246, with autopsyproven DLB pathology in a region of 9.2 Mb. Here, we describe the ascertainment of additional
DR246 family members and significant finemapping of the DLB locus to 3.3 Mb based on
informative meiotic recombinants. Extensive sequencing of the 42 positional candidate genes within
the DLB region did not identify a simple pathogenic mutation that co-segregated with disease in
family DR246. Also high resolution analysis of copy number variations in the DLB locus did not
provide evidence for a complex mutation. In conclusion, we confirmed the DLB locus at 2q35-q36
as a genetic entity but candidate gene-based sequencing and copy number variation analysis did not
identify the pathogenic mutation in family DR246. Other detection strategies will be needed to
reveal the underlying mutation explaining the linkage of DLB to 2q35-q26. Possibly the disease
mutation in this family acts through a more complex mechanism than generally envisaged for
monogenic disorders. Nevertheless, identifying the first familial DLB gene is likely to contribute an
entry point into the pathogenic cascades underlying DLB pathology (Meeus et al., 2010a).
III. PHENOTYPE-GENOTYPE CORRELATIONS IN NEUROMUSCULAR DISEASES
III. 1 From Neurogenetics
A. Peripheral Neuropathies (V. Timmerman and co-workers)
Damage to specific neuronal populations is a central feature of the disease process in monogenic
hereditary peripheral neuropathies. The subgroup of distal hereditary motor neuropathies (distal
HMN) is characterized by degeneration of motor neurons and their axons in the peripheral nervous
system. Distal HMN patients display progressive muscle weakness and atrophy in lower legs and
feet from their childhood or adolescence. The disease is clinically and genetically heterogenous and
is divided into different subtypes based on the inheritance pattern. Despite the absence of sensory
symptoms, distal HMN shows strong clinical resemblance with the axonal form of Charcot-MarieTooth disease (CMT2). Selective degeneration of motor neuronen is also typical for sporadic
amyotrophic lateral sclerosis (ALS). In contrast to distal HMN, sporadic ALS is a complex disease
caused by different genetic risk factors and environmental factors. The underlying mechanisms of
selective degeneration of motor neurons in both conditions is still not known. The identification of
gene mutations linked to hereditary forms of these conditions, can provide insight in the underlying
disease processes.
Up to 2008, mutations in six different genes had been identified for autosomal dominant distal
HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1
(HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy
(BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C
(VAPB) was found in several Brazilian families with complex and atypical forms of autosomal
dominantly inherited motor neuron disease. We have investigated the distribution of mutations in
these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor
neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and
SETX in 17 patients of whom 10 have been previously reported. No mutations were found in
Scientific Report Institute Born-Bunge 2010. Page 19
GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1,
BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal
HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provided
evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a
large cohort of familial and isolated distal HMN patients, clearly confirmed the genetic and
phenotypic heterogeneity of distal HMN and provided a basis for the development of algorithms for
diagnostic mutation screening in this group of disorders (Dierick et al., 2008). One of the patients
was separately published as a case report. This person displayed an autosomal dominant congenital
spinal muscular atrophy, without a mutation in one of the known genes (Reddel et al., 2008).
Based on electrophysiological and histopathological criteria, two types of CMT can be identified:
CMT type 1 (CMT1) is a demyelinating form characterized by reduced nerve ccondution velocities
(NCVs <38m/s), while CMT type 2 (CMT2) is the axonal form characterized by normal of only
slightly reduced NCVs. In some CMT families, patiënts can display highly variable NCVs; from
normal to severily reduced NCVs, leading to a phenotype that overlaps between CMT1 and CMT2.
This form of CMT is decribed as intermediairy CMT. Dominant-intermediate Charcot-Marie-Tooth
neuropathy (DI-CMT) is characterized by axonal degeneration and demyelination of peripheral
motor and sensory neurons. Three dominant mutations in the YARS gene, encoding tyrosyl-tRNA
synthetase (TyrRS), have so far been associated with DI-CMT type C. The molecular mechanisms
through which mutations in YARS lead to peripheral neuropathy are currently unknown, and animal
models for DI-CMTC are not yet available. Here, we report the generation of a Drosophila model of
DI-CMTC: expression of the 3 mutant--but not wild type--TyrRS in Drosophila recapitulates
several hallmarks of the human disease, including a progressive deficit in motor performance,
electrophysiological evidence of neuronal dysfunction and morphological signs of axonal
degeneration. Not only ubiquitous, but also neuron-specific expression of mutant TyrRS, induces
these phenotypes, indicating that the mutant enzyme has cell-autonomous effects in neurons.
Furthermore, biochemical and genetic complementation experiments revealed that loss of
enzymatic activity is not a common feature of DI-CMTC-associated mutations. Thus, the DI-CMTC
phenotype is not due to haploinsufficiency of aminoacylation activity, but most likely to a gain-offunction alteration of the mutant TyrRS or interference with an unknown function of the WT
protein. Our results also suggest that the molecular pathways leading to mutant TyrRS-associated
neurodegeneration are conserved from flies to humans (Storkebaum et al., 2009).
Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically
heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or
predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations
have been identified in seven genes: two genes for autosomal dominant (SPTLC1 and RAB7) and
five genes for autosomal recessive forms of HSAN (WNK1/HSN2, NTRK1, NGFB, CCT5 and
IKBKAP). We performed a systematic mutation screening of the coding sequences of six of these
genes on a cohort of 100 familial and isolated patients diagnosed with HSAN. In addition, we
screened the functional candidate gene NGFR (p75/NTR) encoding the nerve growth factor
receptor. We identified disease-causing mutations in SPTLC1, RAB7, WNK1/HSN2 and NTRK1
in 19 patients, of which three mutations have not previously been reported. The phenotypes
associated with mutations in NTRK1 and WNK1/HSN2 typically consisted of congenital
insensitivity to pain and anhidrosis, and early-onset ulcero-mutilating sensory neuropathy,
respectively. RAB7 mutations were only found in patients with a Charcot-Marie-Tooth type 2B
(CMT2B) phenotype, an axonal sensory-motor neuropathy with pronounced ulcero-mutilations. In
SPTLC1, we detected a novel mutation (S331F) corresponding to a previously unknown severe and
early-onset HSAN phenotype. No mutations were found in NGFB, CCT5 and NGFR. Overall
disease-associated mutations were found in 19% of the studied patient group, suggesting that
additional genes are associated with HSAN. Our genotype-phenotype correlation study broadens the
spectrum of HSAN and provides additional insights for molecular and clinical diagnosis (Rotthier et
al., 2009). In this study a new NTRK1 mutation causing Congenital insensitivity to pain with
Scientific Report Institute Born-Bunge 2010. Page 20
anhidrosis (CIPA). We reported the clinical course of a 7-year-old girl with CIPA and proven
NTRK1 mutation. In addition to recurrent dislocation of the left hip joint and avascular necrosis of
the left talus, the patient also presented with recurrent infections secondary to
hypogammaglobulinemia, a feature not previously known to be associated with CIPA. The patient
was treated with regular administration of intravenous immunoglobulins. Conservative treatment of
the recurrent left hip dislocation by cast immobilization and bracing was implemented to stabilize
the joint. The implication of the immune system of the reported patient broadens the clinical
phenotype associated with NTRK1 mutations (Kilic et al., 2009).
Hereditary sensory neuropathy type 1 (HSAN I) is an autosomal dominant inherited
neurodegenerative disorder of the peripheral nervous system associated with mutations in the
SPTLC1 subunit of the serine palmitoyltransferase (SPT). Four missense mutations (C133W,
C133Y, V144D and G387A) in SPTLC1 were reported to cause HSAN I. SPT catalyses the
condensation of Serine and Palmitoyl-CoA, which is the first and rate-limiting step in the de novo
synthesis of ceramides. Earlier studies showed that C133W and C133Y mutants have a reduced
activity, whereas the impact of the V144D and G387A mutations on the human enzyme was not
tested yet. In this paper, we show that none of the HSAN I mutations interferes with SPT complex
formation. We demonstrate that also V144D has a reduced SPT activity, however to a lower extent
than C133W and C133Y. In contrast, the G387A mutation showed no influence on SPT activity.
Furthermore, the growth phenotype of LY-B cells--a SPTLC1 deficient CHO cell line--could be
reversed by expressing either the wild-type SPTLC1 or the G387A mutant, but not the C133W
mutant. This indicates that the G387A mutation is most likely not directly associated with HSAN I.
These findings were genetically confirmed by the identification of a nuclear HSAN family which
showed segregation of the G387A variant as a non-synonymous SNP (Hornemann et al., 2009). Our
recent research demonstrates that mutations in the second subunit of SPT, SPTLC2, likewise cause
HSAN-I. Functional studies show that mutations in both subunits act in a similar way, namely by
reducing the canonical SPT activity in vitro and increasing the levels of the atypical deoxysphingoid
bases (DSBs) 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine. Of note, the accumulation of
DSBs was found in all plasma samples of HSAN-I patients tested thus far, but this was not the case
for all HEK293T cell lines stably expressing the mutant proteins. Our results confirm that the
increased formation of DSBs is a key feature of HSAN-I, which provides opportunities for these
compounds to serve as biomarkers. The absence of a consistent increase in DSBs in cell lines
expressing the mutant proteins warrants for caution in the interpretation of in vitro data (Rotthier et
al. 2010).
Besides the identification of mutations in known genes for HSAN, we also identified mutations in a
new gene, FAM134B. Hereditary sensory and autonomic neuropathy type II (HSAN II) leads to
severe mutilations because of impaired nociception and autonomic dysfunction. We showed that
loss-of-function mutations in FAM134B, encoding a newly identified cis-Golgi protein, causes
HSAN II. Fam134b knockdown results in structural alterations of the cis-Golgi compartment and
induces apoptosis in some primary dorsal root ganglion neurons. This implicates FAM134B as
critical in long-term survival of nociceptive and autonomic ganglion neurons (Kurth et al., 2009).
The HSPB1 and HSPB8 are widely expressed genes and code for chaperone proteins with essential
cellular function. They protect cells from stress situations by refolding and protecting other proteins
and cellular components. Motor neurons seem to be particularly vulnerable to mutations in HSPB1
and HSPB8 and thus cause the neurodegeneration. The mutant small HSP proteins may interfere
with neuronal pathways by the formation of protein aggregates which could disrupt axonal cargo
transport, affect neuronal cell survival or hamper their chaperone function. We have now
investigated the influence of HSPB1 mutations on the basic biochemical properties of this protein
using neuronal cell lines stably expressing either wild-type or mutant HSPB1 variants. Surprisingly,
three mutations presented higher in vivo chaperone activity when compared to the wild-type
protein. The enhanced activity of these mutations was accompanied by an increased fraction of the
protein residing in a monomeric state. Consistently, analysis of the predicted protein structure of
Scientific Report Institute Born-Bunge 2010. Page 21
HSPB1 suggested a mechanism for the monomeric tendency of hyperactive mutants. Furthermore,
we were able to show that heat shock-induced activation of the wild-type HSPB1 is also
accompanied by a similar increase in the fraction of the protein residing in the monomeric state, at
the expense of the dimer fraction, indicating that the ratio between monomeric and dimeric HSPB1
is a key determinant for the activity of the protein (Almeida-Souza et al., 2010).
The mechanism through which mutant HSPB8 leads to a specific motor neuron disease phenotype
is currently unknown. To address this question, we compared the effect of mutant HSPB8 in
primary neuronal and glial cell cultures. In motor neurons, expression of both HSPB8 K141N and
K141E mutations clearly resulted in neurite degeneration, as manifested by a reduction in number
of neurites per cell, as well as in a reduction in average length of the neurites. Furthermore,
expression of the K141E (and to a lesser extent, K141N) mutation also induced spheroids in the
neurites. We did not detect any signs of apoptosis in motor neurons, showing that mutant HSPB8
resulted in neurite degeneration without inducing neuronal death. While overt in motor neurons,
these phenotypes were only very mildly present in sensory neurons, and completely absent in
cortical neurons or glial cells. These findings show that despite the ubiquitous presence of HSPB8,
only motor neurons appear to be affected by the K141N and K141E mutations which explains the
predominant motor neuron phenotype in distal HMN and CMT2L (Irobi et al., 2010).
Toll-like receptors (TLRs) comprise a family of evolutionary conserved pattern recognition
receptors that act as a first defense line in the innate immune system. Upon stimulation with
microbial ligands, they orchestrate the induction of a host defense response by activating different
signaling cascades. Interestingly, they appear to detect the presence of endogenous signals of
danger as well and as such, neurodegeneration is thought to trigger an immune response through
ligation of TLRs. Though recent data report the expression of various TLRs in the central nervous
system, TLR expression patterns in the peripheral nervous system (PNS) have not been determined
yet. We observed that Schwann cells express relatively high levels of TLRs, with especially TLR3
and TLR4 being prominent. Sensory and motor neurons hardly express any TLR at all. Through the
use of NF-κB signaling as readout, we could show that all TLRs are functional in Schwann cells
and that bacterial lipoprotein (BLP), a ligand for TLR1/TLR2 receptors, yields the strongest
response. In sciatic nerve, basal levels of TLRs closely reflect the expression patterns as determined
in Schwann cells. TLR3, TLR4 and TLR7 are majorly expressed, pointing to their possible role in
immune surveillance. Upon neurodegeneration, TLR1 becomes strongly induced, while most other
TLR expression levels remain unaffected. Altogether, we found that similar to microglia in the
brain, Schwann cells might act as sentinel cells in the PNS. Furthermore, neurodegeneration induces
a shift in TLR expression pattern, most likely illustrating specialized functions of TLRs in basal
versus activated conditions of the peripheral nerve (Goethals et al., 2010).
B. Progressive external ophtalmologies and mitochondrial conditions (P. De Jonghe, A.
Jordanova, G. Van Goethem and co-workers)
In our research focusing on molecular genetic aspects of mitochondrial conditions, we described a
Saudi Arabian family, which presented with adult onset autosomal dominant progressive external
ophthalmoplegia (adPEO) complicated by late onset reversible failure of the CNS, respiratory,
hepatic, and endocrine systems. Clinical findings were suggestive of mitochondrial dysfunction and
multiple mitochondrial DNA deletions were demonstrated on long range and real time polymerase
chain reaction assays but not on Southern blotting. The disorder is caused by a novel heterozygous
PEO1 mutation predicting a Leu360Gly substitution in the twinkle protein. The peculiar clinical
presentation expands the variable phenotype observed in adPEO and Twinkle gene mutations
(Bohlega et al., 2009).
We have contributed to the European Federation of Neurological Sciences (EFNS) guidelines
designed to provide practical help for the general neurologist to make appropriate use of molecular
Scientific Report Institute Born-Bunge 2010. Page 22
genetics for diagnosing mitochondrial disorders (MIDs), which gain increasing attention and are
more frequently diagnosed due to improved diagnostic tools. The guidelines summarise the
possibilities and limitations of molecular genetic diagnosis of MIDs and provide practical
recommendations and diagnostic criteria in accordance with the EFNS Scientific Committee to
guide the molecular diagnostic work-up of MIDs (Finsterer et al., 2009).
C. Congenital myopathies (P. De Jonghe, A. Jordanova, G. Van Goethem and co-workers)
We prospectively assessed magnetic resonance (MR) imaging findings of lower limb musculature
in an axonal Charcot-Marie-Tooth disease (CMT2) pedigree due to mutation in the dynamin 2 gene
(DNM2). The series comprises a proband patient aged 55 years and her two affected daughters aged
32 and 23. MR imaging study included T1- and fat suppressed T2-weighted spin-echo sequences.
MR imaging study showed extensive fatty infiltration of all calf muscle compartments with relative
preservation of the deep posterior one. Fatty muscle infiltration increased distally in 19 out of 66
(23%) visualized calf muscles in the three patients, but this percentage increased to 64% in the
youngest and least severe patient. Muscle edema without contrast enhancement was present in 23%
of calf muscles. There was massive fatty atrophy of foot musculature. We conclude that MR
imaging study accurately depicts lower limb muscle involvement in CMT2 caused by DNM2
mutation (Gallardo et al., 2008).
Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin
2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in
34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type
B families in whom a dynamin 2 mutation had been identified: Gly358Arg (Spain);
Asp551_Glu553del; Lys550fs (North America); Lys558del (Belgium); Lys558Glu (Australia, the
Netherlands) and Thr855_Ile856del (Belgium). The Gly358Arg and Thr855_Ile856del mutations
were novel, and in contrast to the other Charcot-Marie-Tooth-related mutations in dynamin 2,
which are all located in the pleckstrin homology domain, they were situated in the middle domain
and proline-rich domain of dynamin 2, respectively. We report the first disease-causing mutation in
the proline-rich domain of dynamin 2. Patients with a dynamin 2 mutation presented with a classical
Charcot-Marie-Tooth phenotype, which was mild to moderately severe since only 3% of the
patients were wheelchair-bound. The mean age at onset was 16 years with a large variability
ranging from 2 to 50 years. Interestingly, in the Australian and Belgian families, which carry two
different mutations affecting the same amino acid (Lys558), Charcot-Marie-Tooth cosegregated
with neutropaenia. In addition, early onset cataracts were observed in one of the Charcot-MarieTooth families. Our electrophysiological data indicate intermediate or axonal motor median nerve
conduction velocities (NCV) ranging from 26 m/s to normal values in four families, and less
pronounced reduction of motor median NCV (41-46 m/s) with normal amplitudes in two families.
Sural nerve biopsy in a Dutch patient with Lys558Glu mutation showed diffuse loss of large
myelinated fibres, presence of many clusters of regenerating myelinated axons and fibres with focal
myelin thickenings--findings very similar to those previously reported in the Australian family. We
conclude that dynamin 2 mutations should be screened in the autosomal dominant Charcot-MarieTooth neuropathy families with intermediate or axonal NCV, and in patients with a classical mild to
moderately severe Charcot-Marie-Tooth phenotype, especially when Charcot-Marie-Tooth is
associated with neutropaenia or cataracts (Claeys et al., 2009).
Autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy type 4H (CMT4H) manifests
early onset, severe functional impairment, deforming scoliosis, and myelin outfoldings in the nerve
biopsy. Mutations in the FGD4 gene encoding the Rho-GTPase guanine-nucleotide-exchange-factor
frabin were reported in five families. We characterized a novel mutation in FGD4 and described the
related phenotype. The proband disclosed a moderately severe, scarcely progressive CMT,
markedly slowed nerve conduction velocities, and a demyelinating neuropathy characterized by
prominent myelin outfoldings. Mutational analysis disclosed a c.1762-2a>g transition in the spliceScientific Report Institute Born-Bunge 2010. Page 23
acceptor site of intron 14, which was predicted to cause a truncated frabin (p.Tyr587fsX14). The
report confirms genetic heterogeneity of FGD4, demonstrates that CMT4H has variable functional
impairment, and suggests that frabin plays a crucial role during myelin formation (Fabrizi et al.,
2009).
Gonadal dysgenesis with normal male karyotype (46XY) is a sexual differentiation disorder. So far
three patients have been reported presenting the association of 46XY gonadal dysgenesis with
peripheral neuropathy. Examination of sural nerves revealed minifascicle formation in two of them.
In one patient, a mutation was found in desert hedgehog homolog (Drosophila), a gene important in
gonadal differentiation and peripheral nerve development. We studied neuropathological and
molecular genetic aspects of a patient with 46XY gonadal dysgenesis and peripheral neuropathy.
Examination of a sural nerve biopsy specimen revealed an axonal neuropathy with pronounced
axonal loss, limited signs of axonal regeneration and no minifascicle formation. A normal male
karyotype was found (46XY) without micro-deletions in the Y chromosome. No mutations were
found in the sex determining region Y gene, peripheral myelin protein 22, Myelin Protein Zero,
Gap-Junction protein Beta 1, Mitofusin 2 or desert hedgehog homolog. The absence of minifascicle
formation and the absence of a mutation in desert hedgehog homolog in this patient with gonadal
dysgenesis and peripheral neuropathy expand the clinical and genetic heterogeneity of this rare
entity (Baets et al., 2009).
EPILEPSIE-GERELATEERD ONDERZOEK
Vanuit Neurogenetica
The phenotypes associated with SCN1A mutations are Dravet syndrome, Generalized Epilepsy with
Febrile Seizures plus (GEFS+) and hemiplegic migrain.
The neuronal voltage-gated sodium channel Na(v)1.1 encoded by the SCN1A gene plays an
important role in the generation and propagation of action potentials in the central nervous system.
Altered function of this channel due to mutations in SCN1A leads to hypersynchronous neuronal
discharges resulting in seizures or migrainous attaques. A large number of distinct sequence
variants in SCN1A are associated with diverse epilepsy and migraine syndromes. We developed an
online and freely available database containing all reported sequence variants in SCN1A
(http://www.molgen.ua.ac.be/SCN1AMutations/). We verified 623 distinct sequence variants, listed
them using standard nomenclature for description and classified them according to their putative
pathogenic nature. We provided links to relevant publications and information on the associated
phenotype. The database can be queried using cDNA or protein position, phenotype, variant type or
publication. By listing all SCN1A variants in a comprehensive manner, this database will facilitate
interpretation of newly identified sequence variants and provide better insight into the genotypephenotype relations of the growing number of SCN1A mutations (Claes et al., 2009).
We reported the first patient with Dravet syndrome associated with a recessive mutation in SCN1B
(p.R125C). Biochemical characterization of p.R125C in a heterologous system demonstrated little
to no cell surface expression despite normal total cellular expression. This occurred regardless of
coexpression of Na(v)1.1 alpha subunits. Because the patient was homozygous for the mutation,
these data suggest a functional SCN1B null phenotype. To understand the consequences of the lack
of beta1 cell surface expression in vivo, hippocampal slice recordings were performed in Scn1b(-/-)
versus Scn1b(+/+) mice. Scn1b(-/-) CA3 neurons fired evoked action potentials with a significantly
higher peak voltage and significantly greater amplitude compared with wild type. However, in
contrast to the Scn1a(+/-) model of Dravet syndrome, we found no measurable differences in
sodium current density in acutely dissociated CA3 hippocampal neurons. Whereas Scn1b(-/-) mice
seize spontaneously, the seizure susceptibility of Scn1b(+/-) mice was similar to wild type,
suggesting that, like the parents of this patient, one functional SCN1B allele is sufficient for normal
Scientific Report Institute Born-Bunge 2010. Page 24
control of electrical excitability. We conclude that SCN1B p.R125C is an autosomal recessive cause
of Dravet syndrome through functional gene inactivation (Patino et al., 2009).
Absence epilepsies of childhood are heterogeneous with most cases following complex inheritance.
Those cases with onset before 4 years of age represent a poorly studied subset. We screened 34
patients with early-onset absence epilepsy for mutations in SLC2A1, the gene encoding the GLUT1
glucose transporter. Mutations leading to reduced protein function were found in 12% (4/34) of
patients. Two mutations arose de novo, and two were familial. These findings suggest GLUT1
deficiency underlies a significant proportion of early-onset absence epilepsy, which has both
genetic counseling and treatment implications because the ketogenic diet is effective in GLUT1
deficiency (Suls et al., 2009).
Incidence rates of epilepsy in children are highest during the first year of life. Most frequently,
epilepsy results from a metabolic or structural defect in the brain. However, some infants have
clearly delineated epilepsy syndromes for which no underlying etiology can be identified except for
a genetic predisposition. We reviewed the current knowledge on the genetics of epilepsy syndromes
starting in the first year of life. We focus on those epilepsy syndromes without a clear structural or
metabolic etiology. This knowledge has consequences for clinical practice as it opens new
perspectives for genetic testing, improving early diagnosis, and facilitating genetic counseling.
(Deprez et al., 2009).
IV. METABOLIC CONDITIONS WITH NEUROLOGICAL COMPLICATIONS
The Laboratory of Neurochemistry and Behaviour continued its study of biochemical and
pathophysiological paramaters linked to hereditary disorders of the urea cycle and acquired renal
failure.
In collaboration with Raymond Vanholder (Nephrological department of the University Hospital of
Ghent) we reviewed the guanidino compounds as candidate uremic neurotoxins (De Deyn et al.,
2009). Our collaborative scientific research with the same group was concentrated on the
dialysibility of specific guanidino compounds increased in the physiological fluids and tissue of
patients with renal insufficiency. Before we found already that the dialysibility of urea, creatinine
and other guanidino compounds are different. A profound study on the dialysibility of the specific
guanidino compounds increased in the body fluids and tissue of the patients next to urea was done.
This study was necessary to obtain a better understanding of the specific dialysibility of each
specific compound in order to optimalize the future dialysis procedures to eliminate these
accumulated compounds as much as possible from renal insufficient patients. The complex and
compartmental behaviour of these water soluble uremic retention solutes has been shown after the
determination of the concentration of these specific compounds in plasma and erythrocytes of
patients (Eloot et al., 2007). Further we obtained more insight of the impact of increased
haemodialysis frequency and haemodialysis duration on the removal of guanidino compounds: a
much more adaquate clearance of creatinine and methylguanidine was obtained by increasing the
dialysis duration. Increasing the dialysis frequency resulted however in a better clearance of
guanidinosuccinic acid, one of the highly accumulated compounds in patients (Eloot et al., 2009).
Furthermore we highlighted the accumulation of methylguanidine in rats after furosemide
administration and the changement of other guanidino compound levels have been observed after
supplementation of creatine to renal insufficient patients. Methylguanidine is accumulated in body
fluids and tissue of patients with renal insufficiency as a consequence of reduced glomerular
filtration, it is also one of the most proposed candidate neurotoxins in uraemia. A clear increase of
methylguanidine in the body fluids and kidneys of furosemide-treated rats was seen (Levillain et al.,
2008). To prevent loss of muscle mass in patients with renal insufficiency supplementation of
creatine is given. As a consequence the plasma guanidinoacetic acid decreased with 15% due to
inhibition of the creatine-creatinine biosynthesis pathway. The plasma levels of the epileptogenic
Scientific Report Institute Born-Bunge 2010. Page 25
keto- and hydroxyl-analogue of arginine were also increased respectively 3 and 2 times compared to
the levels before supplementation (Taes et al., 2008).
The Laboratory of Neurochemistry and Behaviour of the Institute of Born-Bunge had an of many
years’ standing experience in amino acid analyses. Their expertise concerning urea cycle disorders
is acknowledged internationally. Detailed clinical and biochemical characteristics of patients with
argininemia (last enzymatic deficiency in the urea cycle) were first described following our
diagnosis in our laboratory at the end of the sixties of the former century. In this context our
laboratory always investigated and investigates extensively studies concerning the arginine
metabolism. Therefore a mouse model for argininemia was created by our collaborators from
UCLA. Specific increased catabolites of arginine (guanidino compounds) were observed in plasma
and tissues of the model (Deignan et al., 2008). This model helps us a lot to obtain a better
understanding of the pathobiochemistry and pathophysiology seen in human argininemia. This way
we observed that the increase of arginine levels together with specific catabolites of arginine in
central nervous system of the mouse model as well in post mortem material of human patients is
much less than those seen in periferic organs (Deignan et al., 2010). Therefore the question rises if
other catabolites of arginine like nitric oxide or derivatives of it are not more associated with the
symptomatology seen in patients with argininemia.
V. PHENOTYPICAL CHARACTERIZATION OF (TRANSGENIC) ANIMAL MODELS
NEURODEGENERATIVE CONDITIONS (Neurochemie & Gedrag)
FOR
In-depth behavioural phenotyping of (transgenic) mouse models contributes to the unraveling of the
influence of gene alterations and gene-environment interactions on the pgenotype of different forms
of mental retardation and neurodegeneration, as well as our knowledge of underlying
pathophysiological mechanisms and the identification of therapeutic targets for the development of
novel treatment strategies.
As described in the previous report (2004-2007), the Behavioural Research Unit at the Laboratory
of Neurochemistry and Behaviour has greatly added to the behavioural phenotyping of the APP23
transgenic mouse model for AD and is now mainly focusing on the assessment of BPSD-related
behavioural alterations (BPSD = "behavioural and psychological signs and symptoms of
dementia"). The APP23 model develops pathological features, learning and memory deficits
analogous to dementing patients.
We investigated ingestive behavior in APP23 males of 3, 6 and 12 months using operant
conditioning boxes equipped with an automated pellet feeder and optical lick-o-meter.. In addition,
body weights of a naive male group were longitudinally monitored starting at weaning. Olfactory
acuity was evaluated in mice of different age groups. Although olfactory functioning of APP23
mice appeared intact, they drank more and took more food pellets compared with wild-type
littermates during a 1-week registration period. From the age of 4.5 weeks onward, APP23 males
weighed significantly less than their control littermates, whereas this difference became more
prominent with increasing age. Our results suggest the presence of a hypermetabolic state in this
model (Vloeberghs et al., 2008b).
Learning and memory were previously assessed in the APP23 model using the Morris water maze
(MWM) and passive avoidance learning. In search of a non-spatial alternative for assessment of
hippocampus-dependent memory, we evaluated an odour paired-associate test, which is based on
learning an association between two sets of odours. The protocol includes a shaping phase, in which
the animals learn to dig up a reward, a preliminary training phase and a training phase, where the
actual association is learned. Subsequently, mice are tested for transitive inference and subjected to
a symmetry test. Impairment was seen in the APP23 mice, in comparison with wild type mice, in
training; however, both groups failed the transitivity and symmetry test. Possible explanations for
Scientific Report Institute Born-Bunge 2010. Page 26
this discrepancy with earlier published results are the advanced age of the mice or the C57Bl/6J
background, in which the model was established (Van Dijck et al., 2008).
Valid animal models are indispensable in the drug discovery pipeline for dementia. Transgenic
APP23 mice model Alzheimer's disease patients' memory deficits and additionally present with
various behavioural disturbances, such as aggressive behaviour. The present study investigated and
confirmed significant sensitivity of the model to the aggression-lowering ability of the antipsychotic
agent risperidone (CAS 106266-06-2). The sensitivity for such anti-aggressive action contributes to
the therapeutic predictive validity of the APP23 model of Alzheimer's disease, which can be used as
a pre-clinical screening tool for the identification of novel anti-aggressive agents (Vloeberghs et al.,
2008a).
The role of animal models in dementia research and the drug discovery pipeline for Alzheimer’s
disease in particular, were reviewed in a book entitled “Animal models of dementia”, edited by De
Deyn PP and Van Dam D (2010), and in an invited review by Van Dam & De Deyn, accepted for
publication in Br. J. Pharmacol.
The potential disease-modifying efficacy of drugs currently used for the symptomatic treatment of
AD are under debate. The interest for acetylcholinesterase inhibitors in the treatment of AD has
been greatly renewed owing to the discovery of a broad range of additional cholinergic and noncholinergic effects, exploitable to maximize the efficacy of these drugs beyond merely improving
intellectual functions at the symptomatic level. The age-dependent cognitive decline in the valid
APP23 transgenic mouse model for Alzheimer's disease was employed to evaluate diseasemodifying efficacy of chronic treatment with donepezil. At age 6 weeks, heterozygous APP23 mice
and control littermates were subcutaneously implanted with osmotic pumps delivering saline or
donepezil (0.27 or 0.58 mg/kg per day). After 2 months of treatment, a 3-week wash-out period was
allowed to prevent bias from sustained symptomatic effects before cognitive evaluation in the
MWM commenced. Chronic donepezil (0.27 mg/kg per day) treatment improved spatial accuracy in
APP23 mice as to reach the same level of performance as wild-type control animals on this complex
visual-spatial learning task (Van Dam et al., 2008). A similar study design was employed to assess
disease-modifying efficacy of ibuprofen in the APP23 mouse model (Van Dam et al., 2010).
NAPVSIPQ (NAP) is a small, active fragment of activity-dependent neuroprotective protein that
has neuroprotective and memory enhancing properties at very low concentrations. Twelve-monthold male heterozygous APP23 mice and their wild-type control littermates were intraperitoneally
injected with 0.3 microg NAP/g body weight or with saline vehicle for 22 consecutive days.
Cognitive performance training in the MWM started on day 8 of treatment. The internal validity of
our study was demonstrated by the fact that the APP23 mice performed significantly worse in the
MWM than wild-type animals. Treatment with NAP, however, did not exert any significant effects
on MWM performance. Although we failed to show significant memory enhancing effects in this
study, NAP might be a promising peptide for disease-modifying therapy in neurodegenerative
disease, but short-term effects are probably not to be expected. Also, most likely, treatment should
start in an early stage, i.e. before full-blown pathology is eminent, and the necessary treatment
period should enclose several months (Van Dijck et al., 2009a).
The development of AD is closely connected with cholesterol metabolism. Cholesterol increases the
production and deposition of Abeta peptides that result in the formation of amyloid plaques, a
hallmark of the pathology. In the brain, cholesterol is synthesized in situ but cannot be degraded nor
cross the blood-brain barrier. The major exportable form of brain cholesterol is 24Shydroxycholesterol, an oxysterol generated by the neuronal cholesterol 24-hydroxylase encoded by
the CYP46A1 gene. We report that the injection of adeno-associated vector (AAV) encoding
CYP46A1 in the cortex and hippocampus of APP23 mice before the onset of amyloid deposits
markedly reduces Abeta peptides, amyloid deposits and trimeric oligomers at 12 months of age. The
Morris water maze (MWM) procedure also demonstrated improvement of spatial memory at 6
months, before the onset of amyloid deposits. AAV5-wtCYP46A1 vector injection in the cortex and
Scientific Report Institute Born-Bunge 2010. Page 27
hippocampus of amyloid precursor protein/presenilin 1 (APP/PS) mice after the onset of amyloid
deposits also reduced markedly the number of amyloid plaques in the hippocampus, and to a less
extent in the cortex, 3 months after the injection. Our data demonstrate that neuronal overexpression
of CYP46A1 before or after the onset of amyloid plaques significantly reduces Abeta pathology in
mouse models of AD (Hudry et al., 2009).
In 2005, we described important neurotransmitter alterations in specific brain regions of the APP23
model, including changes in the noradrenergic system. The integrity of the locus coeruleus (LC)
noradrenergic system was studied in the APP23 model at the age of 3, 6 and 12 months through
quantification of tyrosine hydroxylase (TH) mRNA expression. Despite the previous study
suggesting alterations in the noradrenergic transmission system of APP23 mice, the current study
failed to show altered TH-positive neuronal numbers or expression in LC noradrenergic neurons of
APP23 mice versus wild-type (WT) littermates. However, the present study did demonstrate an agedependent effect on TH mRNA expression. Both the number of TH-containing neurons and the
amount of TH-positive grains/neuron significantly increased between the age of 3 and 6 months
with no difference between 6 and 12 months. These observations indicate that any study comparing
the noradrenergic system between WT (C57Bl/6) and experimental mice must strictly choose the
age to be tested and limit age differences between control and experimental groups to the absolute
minimum. More importantly, when long-term therapeutic interventions targeting the noradrenergic
system are applied to mouse models, and related parameters are studied longitudinally, care should
be taken to distinguish between potential therapeutic and strain-specific developmental or agerelated alterations (Szot et al., 2009). Using HPLC, the region-spcific concentation biogenic amines
and metabolites in APP23 and WT mice brain was linked to the animals’ performance in an
isolation-induced resident-intruder aggression protocol. Matrix correlation is applied to search for
the potenial link between altered neurotransmitter levels or turnover and increased male aggression
in the APP23 mice (Manuscript in preparation).
Within the framework of an SBO programme, the effects of centrally administrated obestatin on
eating and drinking behaviour were studied. Obestatin is a ghrelin-associated peptide hormone with
presumed anorexigenic and inhibitory effect on gastric propulsive motility activity. Recent
literature, however, discloses much contestation over satiety and gastrointestinal motility-related
functionalities of obestatin. In addition, antidipsinogenic effects in rodents by obestatin were
recently reported. The present study was set up to bring more clarity into the contested effects of
obestatin on food and water intake. Additionally, the stability of obestatin in brain tissue
homogenate was investigated. The in vitro incubation of obestatin in brain homogenates revealed
disappearance half-life times of 19 min for crude brain homogenate to 27 min for brain membrane
homogenate. For the behavioural studies, male C57Bl/6 mice were intracerebroventricularly treated
with 0.2 nmol murine amidated obestatin or vehicle at the age of 3 months. An additional group of
mice was treated with 0.3 nmol of corticotropin releasing factor (CRF) as a positive control of
suppression of food intake. Food and water intake were studied over a period of 5 h in metabolic
cages. Under our experimental conditions, no suppressive effects of obestatin on food or water
intake were observed, whereas CRF evoked a significant suppression of food intake, which proves
the internal validity of the study design (Van Dijck et al., 2009b).
In collaboration with the Belgian Nuclear Research Centre (SCK-CEN, Mol), we studied the effects
of prenatal exposure to low doses of ionising radiation on cognitive and behavioural parameters in
the adult offspring. Exposure on E12, i.e. the embryonic development day on which the
hippocampus is formed in the mouse, caused severe cognitive deficits in 3-month-old C57BL/6
mice, as tested in the MWM (Manuscript in preparation).
The role of alterered expression of GABAergic system components in the fragile X syndrome and
fragile X associated tremor/ataxia syndrome (FXTAS) was reviewed (D’Hulst et al., 2009).
The striatum is the major input structure of basal ganglia and is involved in adaptive control of
behaviour through the selection of relevant informations. Dopaminergic neurons that innervate
Scientific Report Institute Born-Bunge 2010. Page 28
striatum die in Parkinson disease, leading to inefficient adaptive behaviour. Neuronal activity of
striatal medium spiny neurons (MSN) is modulated by dopamine receptors. Although dopamine
signalling had received substantial attention, consequences of dopamine depletion on MSN intrinsic
excitability remain unclear. Here we show, by performing perforated patch clamp recordings on
brain slices, that dopamine depletion leads to an increase in MSN intrinsic excitability through the
decrease of an inactivating A-type potassium current, I(A). Despite the large decrease in their
excitatory synaptic inputs determined by the decreased dendritic spines density and the increase in
minimal current to evoke the first EPSP, this increase in intrinsic excitability resulted in an
enhanced responsiveness to their remaining synapses, allowing them to fire similarly or more
efficiently following input stimulation than in control condition. Therefore, this increase in intrinsic
excitability through the regulation of I(A) represents a form of homeostatic plasticity allowing
neurons to compensate for perturbations in synaptic transmission and to promote stability in firing.
The present observations show that this homeostatic ability to maintain firing rates within
functional range also occurs in pathological conditions, allowing stabilizing neural computation
within affected neuronal networks (Azdad et al., 2009).
VI. STUDY OF SPONGIFORM ENCEFALOPATHIES (P. CRAS AND CO-WORKERS)
The research of task force 2 focusses on the role of neuroprotective mechanisms in transmissible
spongiform encefalopathies, i.e., Creutzfeldt-Jakob Disease (CJD); bovine spongiform
encephalopathy (BSE) and scrapie. Since 1998 a brain bank containing both fixated and frozen
brain tissue of neuropathologically confirmed CJD patients,a s well as CSF of neuropathologically
confirmed, probable and possible CJD patients is established.
Several molecular subtypes of sporadic CJD have been identified and EEG and CSF biomarkers
have been reported to support clinical diagnosis but with variable utility according to subtype. In
recent years, a series of publications have demonstrated a potentially important role for MRI in the
pre-mortem diagnosis of sporadic CJD. A multi-centre international study aimed to provide a
rationale for the amendment of the clinical diagnostic criteria for sporadic CJD (Zerr et al., 2009).
VII. CARDIOVASCULAR RESEARCH (P.P. VAN BOGAERT AND CO-WORKERS)
A. Characteristics of the Ih current in oocytes
HCN1 and HCN2 channels of the mouse were expressed in Xenopus Laevis oocytes. The
mechanism of progressive decrease of peak amplitude, evoked by a train of voltage-clamp pulses
from -30 to -120 mV (during 1s) was studied by changing the ion composition of the extracellular
solution. The presence of Na+ ions caused blocking of the HCN channel, which could be reversed
again by replacing Na+ ions by K+ ions. This competitive interaction between Na+ and K+ at the
selectivity filter of the HCN channel can explain the reversible decrease of the HCN current in the
Xenopus laevis oocytes. This reversible decrease does not occur in native and HEK293 cells, where
heterological expressiion of HCN channels was applied. In conclusion, HCN channels expressed in
Xenopus laevis have other characteristics than the native Ih channels.
B. Outward currents in mouse dorsal root ganglia (DRG) neurons
Silent voltage-gated K+ (Kv) subunits interact with Kv2 subunits and primarily modulate the
voltage dependence of inactivation of these heterotetrameric channels. Both Kv2 and silent Kv
subunits are expressed in the mammalian nervous system, but little is known about their expression
and function in sensory neurons. This study reports the presence of Kv2.1, Kv2.2, and silent subunit
Kv6.1, Kv8.1, Kv9.1, Kv9.2, and Kv9.3 mRNA in mouse DRG. Immunocytochemistry confirmed
the protein expression of Kv2.x and Kv9.x subunits in cultured small DRG neurons. To investigate
if Kv2 and silent Kv subunits are underlying the delayed rectifier K+ current (IK) in these neurons,
Scientific Report Institute Born-Bunge 2010. Page 29
Kv2-mediated currents were isolated by the extracellular application of rStromatoxin-1 (ScTx) or
by the intracellular application of Kv2 antibodies. Both ScTx- and anti-Kv2.1-sensitive currents
displayed two components in their voltage dependence of inactivation. Together, both components
accounted for approximately two-thirds of IK. A comparison with results obtained in heterologous
expression systems suggests that one component reflects homotetrameric Kv2.1 channels, whereas
the other component represents heterotetrameric Kv2.1/silent Kv channels. These observations
support a physiological role for silent Kv subunits in small DRG neurons (Bocksteins et al., 2009).
C. Sensitivity of fresh DRG neurons and enteric neurons for enteric neurotransmitters
The modulation of submucosal enteric neurons in piglets by cGRP and histamine was studied. Both
compounds modulate the excitability of enteric neurons causing ionic conductance changes. the
effect of enteric neurotransmitters on the electric activity of fresh rat DRG neurons was studied as
well.
Scientific Report Institute Born-Bunge 2010. Page 30
2. COLLABORATIONS
a) National
Benotmane R., (Studiecentrum voor Kernenergie - Centre d'étude de l'Energie Nucléaire, Mol),
study behavioural effects intra-uterin exposure to ionising radiation
Beyaert R. (VIB Departement – Molecular Biomedical Research), Negative regulation of the innate
immune system in the peripheral nerve
Callaerts P. (VIB Department – Molecular and Developmental Genetics), Genetic modifier screen
with the YARS-DI-CMTC Drosophila model & Dominant mutations in the tyrosyl-tRNA
synthetase gene recapitulate in Drosophila features of human Charcot-Marie-Tooth neuropathy
Callaerts P.(VIB Department – Developmental Genetics), Biochemical analysis of TDP43 in
TDP43 Drosophila flies – 2009
Ceulemans B. (Child Neurology, University Hospital Antwerp and University of Antwerp), Family
with juvenile parkinsonism and ATP13A2 mutation
Ceulemans B. (Department of Neurology, University Hospital Antwerp, Antwerp), Genotypephenotype correlations in Inherited Epilepsies.
Chen Ch. (UGent, VIB), analysis N-glycan profiles in AD (human/APP23 mouse model)
De Meyer G, Martinet W (Physiopharmacology, UAntwerpen), development of an APP23 x ApoE
ko model
De Strooper B. (KULeuven), FTD PS1 G183V mutation & Ab42- Ab40 TGFb normalized ELISA
Deforce D. (UGent), Isolation of potential targets modifying Abeta aggregation
Dewilde S., Moens L. (Eiwitchemie, UAntwerpen), behavioural phenotyping of NGB
overexpression mice
Dommisse R (Dept. Chemistry, Applied NMR, UAntwerpen), NMR spectroscopy
Gettemans J. (UGent, VIB): biochemical experiments (HSP22 & YARS)
Haigh J. (VIB Department – Molecular Biomedical Research), HSPB1 and HSPB8 KI/KO
modeling
Hochpied T. (VIB Department – Plant Systems Biology), Knock-in knock-out models
Huylebroeck D. (KULeuven, VIB): in situ hybridisations (SSH experiments)
Jansen A. (Department of Child Neurology, University Hospital VUB), AR GEFS+ in Gypsy
families. Genotype-phenotype correlations in inherited epilepsies
Kooy F. (Medical Geneticc, UAntwerpen), behavioural phenotyping Fmr1 knockout mice
Medical Genetics (UAntwerpen): contribution to histopathological research and/or exchance of
tissue samples
Michotte Y., Smolders I., (VUB), Glutamate transporters in APP23 mouse model for AD
Neuropathology (UZLeuven): contribution to histopathological research and/or exchance of tissue
samples
Paesschen W. (Division of Neurology, University Hospitals Leuven), Genotype-phenotype
correlations in Inherited Epilepsies
Robberecht W. & Van Damme Ph. (Department of Neurology, University Hospital, Gasthuisberg,
Leuven, Belgium), Genotype-phenotype correlations in CMT and HSP
Scientific Report Institute Born-Bunge 2010. Page 31
Robberecht W. & Van Den Bosch L. (VIB Department – Vesalius Research Center), GluR2 in ALS
Robberecht W. (Experimental Neurology, KULeuven), serum and CSF samples of progranulin
mutation carriers
Robberecht W. (VIB Department – Vesalius Research Center), Mutation analysis SACSIN in
ARSACS
Robberecht W. (VIB Department – Vesalius Research Center), Neuronal inclusion protein TDP-43
has no primary genetic role in FTD and ALS & PGRN in microglia
Robberecht W. (VIB Department – Vesalius Research Center), Peripheral neuropathy and 46 XY
gonadal dysgenesis: a heterogenous entity & Mutant heat shock protein HSPB8 induces aggregation
and a pro-apoptotic phenotype in distal motor neuropathy
Rousseau F. (VIB Department – Switch Laboratory), Biophysical characterisation of small HSPB1
and HSPB8
Santens P. (Department of Neurology, University Hospital Ghent and University of Ghent),
Biosampling of FTLD patients for genetic studies
SBO consortium ‘Neuro-TARGET’, Integrated platfom for target identification, validation and drug
discovery applied to neurodegenerative diseases
Schoofs L. (Animal Physiology and Neurobiology, KULeuven), massaspectrometric peptodimocs
analyses of human and animal samples
Schymkowitz J. (VIB Department – Switch Laboratory), Modelling of HSPB1 mutations
Stinissen P. (University of Hasselt), Serum proteomics of the DR8 founder family
Timmermans J.P. (UAntwerpen): Confocal microscopy (HSP22, HSP27 & YARS)
UZGent (Child Neurology and Neuropathology): contribution to histopathological research and/or
exchance of tissue samples
Van den Bergh P. (Service de Neurologie, Cliniques Universitaires Saint-Luc, Université
Catholique de Louvain, Brussels), Genotype-phenotype correlations in CMT and HSP
Van Den Bosch L. (VIB Department – Vesalius Research Center), Molecular pathomechanisms of
HSPB1 and HSPB8 mutations in motor neuropathies: study of protein-protein interactions and
axonal transport in cellular and animal models
Van Dijck P. (KULeuven, VIB): experiments with yeast (YARS)
Van Loo G. (VIB, UGent), behavioural phenotypering A20 ko mice.
Van Roy F. (UGent), Alzheimer & 5-HT7
Van Roy F. (VIB Department – Molecular Biomedical Research), SH-SY5Y-Flp-In cell line &
pFRT/lacZeo construct
Vandenberghe R. (Department of Neurology, University Hospitals Leuven and University of
Leuven), Brain amyloidosis and the brain's response in cognitively intact elderly volunteers &
Biosampling of PD and DLB patients for genetic studies
Vanderlinden A. (Department of Biomedical Sciences, UAntwerp), Transgenic mice - Austrian
APP714
Winderickx J. (Laboratory of Functional Biology, University of Leuven), Prioritizing genes within
the DLB locus based on yeast-deletion screening results
Scientific Report Institute Born-Bunge 2010. Page 32
Wuytack F. and Vangheluwe P. (Laboratory of Cellular Transport Systems, University of Leuven)
Study of the effect of ATP13A2 mutations identified in PD patients on the activity and subcellular
distribution of the protein
b) International
Amouyel P., Lambert J.-C. (Inserm U744, Institut Pasteur de Lille, Université de Lille Nord de
France, Lille, France). European Alzheimer’s Disease Initiative.
Aubourg P. Cartier N. (INSERM, Frankrijk), behavioural phenotyping of MLD and ALD mouse
models and AD-related research in the APP23 model
Auer-Grumbach M. (Institute of Medical Biology and Department of Internal Medicine, Diabetes
and Metabolism, Medical University Graz, Graz, Austria), Genotype-phenotype correlations in
CMT and HSP
Barisic N. (Department of Paediatrics, University of Zagreb, Medical School, University Hospital
Centre Zagreb, Croatia), Genotype-Phenotype correlations in CMT, HSP and Inherited Epilepsies
Battaloglu E. & Parman Y. (Boğaziçi Üniversitesi, Moleküler Biyoloji ve Genetik Bölümü, Bebek,
İstanbul), Identification of novel AR CMT
Berciano J. (Service of Neurology, University Hospital "Marqués de Valdecilla", Santander, Spain),
Genotype-phenotype correlations in CMT. Cloning of the CMT2G gene
Berkovic S. & Scheffer I. (Epilepsy Research Centre, Department of Medicine, University of
Melbourne, Level 1, Neurosciences Building, Heidelberg Repatriation Hospital Austin Health, West
Heidelberg, Australia), Genotype-Phenotype correlations in monogenic forms of epilepsies
Bolino A. (Dulbecco Telethon Institute, San Raffaele Scientific Institute, 20132 Milan, Italy),
KIF13A as candidate gene for CMT
Brice A. (Hôpital de la Salpétrière, Paris, France), MAPT H1 subhaplotypes & haplotyping of
French FTD patients in FTDU-17 candidate region 17q21 & Mutations in a causative gene for FTD
Britain N. (Taconic Farms, Inc., Germantown, NY, USA), Taconic Transgenic Models
Brunt E. (Universitair Ziekenhuis Groningen, Nederland), Ataxine 7 antibodies CM189
Burgers R. (Jackson Laboratories, Bar Harbor, Main, USA), Modelling YARS mutations in mouse
Burgess R. (The Jackson Laboratory, 600 Main St.Bar Harbor, ME 04609, USA), Modifier genes in
GARS
Chance Ph. (University of Washington, Seatle, USA): Identification of SEPT9 mutations in HNA.
Cremers T. (Biomonitoring en Sensoring, Rijksuniversiteit Groningen, The Netherlands),
Neurochemical analyses
de Mendonça A. (Institute of Molecular Medicine, Faculty of Medicine of Lisbon, Portuga),
refinement of the FTDU chromosom locus 17q21 and identification of the disease gene in
Portuguese FTD families
Fabrizi G.M. (Department of Neurological and Vision Sciences, Section of Clinical Neurology,
Verona, Italy), Genotype-phenotype correlation in CMT (Frabin; GDAP1, early onset CMT)
Fabrizi G.M. (Section of Clinical Neurology, Department of Neurological and Visual Sciences,
University of Verona, Italy), Genotyping of FTLD ch9 families
Farrer M. (Mayo Clinic, Jacksonville, USA), tau htSNP haplotyping
Fischbeck K. (NIH, Bethesda, USA), Modelling GARS mutations in Drosophila
Goate A. (Washington University, USA), MAPT H1 SNP haplotyping in PSP patients
Scientific Report Institute Born-Bunge 2010. Page 33
Goebel H.H. (Mainz): neuronal ceroid lipofuscinoses
Haass C. (German Center for Neurodegenerative Diseases (DZNE) & Adolf-Butenandt-Institute,
Biochemistry, Ludwig-Maximilians-University, Munich, Germany). Biomaterial GRN mutation
carriers for drug discovery.
Henry M.W. (Athena Diagnostics, Worcester, Massachusetts, USA), Progranulin mutationds for
dementia diagnosis
Hoh J. (Yale University, New Haven, USA), Genomic DNA of 300 Belgian Parkinson patients and
300 Belgian control subjects for genotyping of 25 SNPs
Houlden H. (University College London, Institute of Neurology, Department of Molecular
Neuroscience, London, UK) Genome wide association study for Multiple System Atrophy
Hornemann T. (Institute for Clinical Chemistry, University Hospital of Zürich, Zürich,
Switzerland), EMBO Short Term Fellowship for the visit of Annelies Rotthier in 2009: SPT
analysis of mutant constructs
Hutton M. (Mayo Clinic, Jacksonville, USA), FTDU-17
Isom L., University of Michigan Medical School, Department of Pharmacology, Ann Arbor,
Michigan, USA), Functional studies of SCN1Ba recessive mutation in Dravet syndrome
Jordanova, A. (Medical University Sofia, Sofia, Bulgaria) Molecular genetic analysis and genotypephenotype correlations in inherited neurological disorders – part neurodegenerative brain diseases
Kaladjeva L. (Laboratory for Molecular Genetics, Western Australian Institute for Medical
Research, UWA Centre for Medical Research, QEII Medical Centre, Hospital Avenue, Nedlands
WA, Australia), Positional cloning of AR epilepsies in Gypsies
Kennerson M. (Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW,
Australia), Missense Mutations in the Copper Transporter Gene ATP7A cause X-linked Distal
Hereditary Motor Neuropathy
Klein W. (Northwestern University, USA), ADDL-specific antibodies
Kochanski A. (Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of
Sciences, Warsaw, Poland), Genotype-phenotype correlations in CMT
Kösler P. (Einzelhandelsfirma Kösler, Rottenburg, Germany), C57BL/6J-TgN (Thy1-APP; Thy1PS1)
Kuhlenbäumer G. (Institut für Experimentelle Medizin, c/o Klinik für Neurologie, Kiel, Germany),
Cloning of the gene for autosomal dominant striatal degeneration. Positional cloning in dHMN and
essential tremor
Kurth I. & Hübner C.A. (Department of Human Genetics, University Medical Center HamburgEppendorf, Hamburg, and Department of Clinical Chemistry, Friedrich-Schiller-Universität Jena,
Germany), Mutations in FAM134B, encoding a newly identified Golgi protein, cause severe
sensory and autonomic neuropathy
Laing N. (Perth), Ferreiro A. (Parijs), Wallgren-Petterson C. (Helsinki), Guicheney P. (Parijs),
Lunardi J. (France): histopathological results of muscles biopsies and DNA samples
Lee V. (University of Pennsylvania, USA), GWA - TDP43/PGRN samples
Lerche H. (Abt. Neurologie mit Schwerpunkt Epileptologie Zentrum für Neurologie Hertie Institut
für Klinische Hirnforschung Universitätsklinikum Tübingen, Tübingen, Germany), Functional
studies of ionchannels (SCN2A, GLUT1). Locus sequencing (Chr16) in Benign Familal Infantile
Seizures and choreoathetosis
Li Y. (Detroit): histopathological results of periferal nerve biopsies and autopsy-derived tissues
Scientific Report Institute Born-Bunge 2010. Page 34
Ludolph A. (University of Ulm, Germany), Localisation of genes and identification of mutated
genes in a German multigenerational dominant ALS family
Maragnaore D. ((NorthShore University HealthSystem, Chicago, IL/ Mayo Clinic, Rochester, MN,
USA), SNCA and survival in PD
Marti H.H. (Institute of Physiology and Pathophysiology, Faculty of Medicine, University of
Heidelberg, Germany), Transgenic mouse line V1 (C57B1/6-TgN(NSEvegf)1651 hhm
McGowan E. (Mayo Foundation for Medical Education and Research, Rochester, USA), 3 BRIAbeta40, 3 BRI-Abeta42 and 3 nontransgenic mice
Mitev V. (Department of Biochemistry, Faculty of Medicine, Medical University of Sofia,
Bulgaria): Hereditary spastic paraplegia (HSP).
Murphy P. (Department of Molecular and Cellular Biochemistry, University of Kentucky,
Lexington, USA) PS1 promotor-luciferase construct to test the hypothesis that leptin signaling is
involved in regulating PS1 expression at the transcriptional level
Nicholson G. & Kennerson M. (The Northcott Neuroscience Laboratory, ANZAC Research
Institute, Concord, Australia; the Molecular Medicine Laboratory, Concord Hospital, Concord,
Australia), Genotype-phenotype correlations in CMT. Cloning of a novel X-linked dHMN gene
Oostra B. (Klinische Genetica, Erasmus MC, Nederland), Fmr1 knockout mice
Ramirez A. (Department of Neurology, University of Lübeck, Germany). Study of the
pathophysiology of ATP13A2 mutations identified in PD patients
Rasic V. (Clinic of Child Neurology and Psychiatry, University of Belgrade, Belgrade, Serbia),
Neuromyotonia. Genotype-phenotype correlations in CMT and HSP
Reitz C. (Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia
University, New York, USA) Meta analyse SORL1.
Revesz T. (Institute of Neurology, London, UK), antibodies against ataxin-7 (CM 189)
Robberecht W. (KULeuven): GluR2 sequence analysis, primary motor neuron cultures, HSP27
Rouleau G. & Rivière J-B. (The Centre of Excellence in Neuromics, CHUM Research Center
Department of Medicine, University of Montreal, Montreal, Quebec, Canada), Cloning of a novel
AR HSN gene
Rüb U. (Klinikum der Johann Wolfgang Göthe Universität, Frankfurt am Main, Germany),
antibodies against ataxin-7 (CM 189)
Saido T. (Laboratory for Proteolytic Neuroscience RIKEN Brain Science Institute Japan) PSEN1
mutant constructs\
Sander Th. (Cologne Center for Genomics, University of Cologne, Cologne, Germany, Department
of Neurology, Charité University Medicine, Humboldt University of Berlin, Berlin, Germany),
GWAS in IGE
Schellenberg G. (University of Seattle, USA), MAPT H1 SNP haplotyping in PSP patients
Schenone A. (University of Genova, Italy): Experimental overexpression of PMP22 in CMT1A rat
nerves via cDNA micro-arrays.
Seeman P. & Haberlova J. (DNA laboratory, Department of Child Neurology, Second School of
Medicine, Charles University Prague, Prague, Czech Republic), Genotype-phenotype correlations
in CMT
Senderek J. (nstitute of Cell Biology, ETH Zürich, Zürich, Switzerland), Identification of novel AR
CMT loci and genes
Scientific Report Institute Born-Bunge 2010. Page 35
Senderek J. (RWTH, Aachen): Identification of the FGD4 gene for CMT4H.
Shy M. & Garbren J. (Department of Neurology, Wayne State University School of Medicine,
Detroit, Michigan, USA), Cloning of a novel gene for X-linked dHMN
Singh N. (Department of Human Genetics, University of Utah, Salt Lake City, USA), SCN9A in
Dravet syndrome
Staufenbiel M. (Novartis Institutes of Biomedical Research Basel, Zwitserland), APP23 model
Stephani U. & Helbig I., Department of Neuropediatrics, Pediatric Epilepsy Genetics Research
Group, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany), CNV analysis in
IGE
Suomalainen A. (Research Program of Neurosciences, Biomedicum-Helsinki, Helsinki, Finland):
PEO and Alpers Syndrome.
Szot P (Northwest Network for Mental Illness Research, Education, and Clinical Center, Veterans
Administration Puget Sound Health Care System, and Department of Psychiatry and Behavioral
Science, University of Washington, Seattle , USA), analyses noradrenergic system
Thomas F. (Spinal Cord Injury/Dysfunction Service, St. Louis Veterans Administration Hospital,
Departments of Neurology & Psychiatry, and Molecular Microbiology & Immunology, Institute for
Molecular Virology, Saint Louis University School of Medicine), Clinical and electrophysiological
aspects of DI-CMTC
Topaloglu H. (Dpartment of Pediatric Neurology, Faculty of Medicine, Hacettepe University,
Ankara, Turkey), Identification of novel AR CMT loci and genes
Tournev I. (Department of Neurology, Medical University-Sofia, Bulgaria; National Genetic
Laboratory, Molecular Medicine Center, Medical University-Sofia, Bulgaria), Cloning of a gene for
distal myopathy. Genotype-phenotype correlations in CMT and Inherited Epilepsies
Van Deerlin V., Chen-Plotkin A.S. (Center for Neurodegenerative Disease Research, Department of
Pathology and Laboratory Medicine and Department of Neurology, University of Pennsylvania
School of Medicine, Philadelphia, PA, USA), Genetic and clinical features of progranulinassociated frontotemporal lobar degeneration
van Minnen J. (Amsterdam): analysis axonal ribosomes employing IBB tissue bank.
Weis J. (nstitut für Neuropathologie, Universitätsklinikum der RWTH, Pauwelsstrasse 30, 52074
Aachen, Germany), Genotype-phenotype correlations in CMT. Morphological study of CMT1B
nerve biopsies
Weiss J. (TWTH, Aachen, Germany), Mutations in genes causing HSAN
Williams J. (MRC Centre for Neuropsychiatric Genetics and Genomics, Department of
Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK).
GERAD Consortium.
Windisch M. (JSW-Research Forschungslabor GmbH), plasmide DNA of neuron-specific mTUB
promoter & transgenic animals
Yokes Baki M. (Haliç Üniversitesi, Moleküler Biyoloji ve Genetik Bölümü, Istanbul, Turkey). PS1
and 2 wild type constructs and vector.
Zabetian C.P. (GRECC S-182, VA Puget Sound Health Care System, Seattle, USA), haplotype
analyses of the LRRK2 gene
Züchner S. (Center for Human Molecular Genomics, John P. Hussman Institute for Human
Genomics, University of Miami Miller School of Medicine; USA), Genotype-phenotype
correlations in CMT and HSP. Whole exome sequencing in HSP
Scientific Report Institute Born-Bunge 2010. Page 36
Züchner S. (Duke University, Durham, USA): MFN2 mutations in axonal neuropathy with optic
atrophy identification of the DNM2 gene for dominant intermediairy CMT.
3. INITIATIVES REGARDING
VALORISATION RESULTS
TRANSFER
OF
KNOWLEDGE,
ANNOUNCEMENT
Transfer of Knowledge and Education
a. Master in Neurosciences (Master in Biomedical Sciences)
b. Master in Biochemistry and Biotechnology
c. Master after Master Biomedical Imaging
d. Postacademic Education Laboratory Animal Sciences
Transfer of Knowledge and Announcements Results
a. http://www.bornbunge.be
4. PAID CO-WORKERS
De Leenheir Eveline
Degree: graduate clinical chemistry A1
Classification: ATP 5.1 (100% till 30/06/2008; 80% from 1/07/2008)
Department: IBB Biobank
Peeters Edith
Degree: graduate clinical chemistry A1
Classification: ATP 5.1 (80%)
Department: IBB Biobank
Franck Frieda
Degree: graduate clinical chemistry A1
Classification: ATP 5.1 (80% till 31/08/2008; 50% from 1/09/2008)
Department: Neurochemistry & Behaviour
Bats Ingeborg
Degree: Photografy A1
Classification: ATP 5.1 (80%)
Department: Electron microscopy and IBB Biobank
In 2009: 3rd and 4rd kwartaal
Possemiers Ilse for 60%
Degree: graduate clinical chemistry A1
Classification: ATP 5.1 (100%)
Department: Neurochemistry & Behaviour
5. EQUIPMENT
N/A
Scientific Report Institute Born-Bunge 2010. Page 37
AND
6. SCIENTIFIC PUBLICATIONS
a1 – papers included in ISI Web of Science
2010 (+ in press, accepted, submitted papers)
1.
Aerts I, Martin JJ, Deyn PP, Van Ginneken C, Van Ostade X, Kockx M, Dua G, Slegers H.
The expression of ecto-nucleotide pyrophosphatase/phosphodi esterase 1 (E-NPP1) is
correlated with astrocytic tumor grade. Clin Neurol Neurosurg. 2010 Dec 30. [Epub ahead of
print] (I.F. 2009: 1.303; cites n/a)
2.
Afawi Z, Suls A, Ekstein D, Kivity S, Neufeld MY, Oliver K, De Jonghe P, Korczy AD,
Berkovic,S.F.: Mild adolescent/adult onset epilepsy and paroxysmal exercise-induced
dyskinesia due to GLUT1 deficiency. Epilepsia 51 (12): 2466-2469 (I.F. 2009: 3.733; cites: 0)
3.
Almeida-Souza L, Goethals S, de Winter V, Dierick I, Gallardo R, Van Durme J, Irobi J,
Gettemans J, Rousseau F, Schymkowitz J, Timmerman V, Janssens S (2010) Increased
monomerization of mutant HSPB1 leads to protein hyperactivity in Charcot-Marie-Tooth
neuropathy. J Biol Chem. 285(17):12778-86. (I.F. 2009: 5.328; cites: 0)
4.
Appenzeller S, Schirmacher A, Halfter H, Bäumer,S., Pendziwiat,M., Timmerman,V., De
Jonghe,P., Fekete,K., Stögbauer,F., Lüdemann,P., Hund-Georgiadis,M., Quabius,E.S.,
Ringelstein,B., Kuhlenbäumer,G. (2010) Autosomal-dominant striatal degeneration is caused
by a mutation in the phosphodiesterase 8B gene. American Journal of Human Genetics 86(1):
83-87 (I.F. 2009: 10.153; cites: 0)
5.
Aretz S, Rautenstrauss B, Timmerman V (2010) Clinical utility gene card for: HMSN/HNPP
HMSN types 1, 2, 3, 6 (CMT1,2,4, DSN, CHN, GAN, CCFDN, HNA). Eur J Hum Genet
18(9): 1070 (I.F. 2009: 3.564; cites: 0)
6.
Aries MJH, Le Bastard N, Debruyne H, Van Buggenhout M, Nagels G, De Deyn PP,
Engelborghs S (2010) Relation between frontal lobe symptoms and dementia severity across
diagnostic categories. Int J Geriatr Psychiatry, 25(11): 1186-1195 (I.F. 2009: 1.981; cites: n/a)
7.
Babiloni C, Visser PJ, Frisoni G, De Deyn PP, Bresciani L, Jelic V, Nagels G, Rodriguez G,
Rossini PM, Vecchio F, Colombo D, Verhey F, Wahlund LO, Nobili F (2010) Cortical
sources of resting EEG rhythms in mild cognitive impairment and subjective memory
complaint. Neurobiol. Aging, 31(10):1787-98 (IF 2009: 5.937; cites: 1)
8.
Baets J, De Jonghe P (2011) Editorial: TRPV4 neuropathies: calcium channel inhibition as a
therapeutic target? Neurology (2011) Epub: 02-Feb-2011 (I.F. 2009: 8.172; cites: n/a)
9.
Baets J, Deconinck T, Goossens D, Van Den Berg P, Dahan K, Schmedding,E., Santens,P.,
Milic-Rasic,V., Van Damme,P., Robberecht,W., De Meirleir,L., Jordanova,A., De Jonghe,P.:
Mutations in SACS cause atypical and late onset forms of ARSACS. Neurology 5(13):11811188 (I.F. 2009: 7.043; cites: 0)
10.
Baillieux H, De Smet HJ, Dobbeleir A, Paquier PF, De Deyn PP, Mariën P (2010) Cognitive
and affective disturbances following focal cerebellar damage in adults: A neuropsychological
and SPECT study. Cortex., 46(7):869-79 (I.F. 2009: 4.058; cites: 5)
11.
Berciano J, Baets J, Gallardo E, Zimon M, Garcia A, López-Laso E, Combarros O, Infante J,
Timmerman V, Jordanova A, De Jonghe P. Reduced penetrance in Charcot-Marie-Tooth
disease type 2C caused by TRPV4 Arg269Cys mutation. Journal of Neurology (Accepted for
Publication) (I.F. 2009: 2.903; cites: n/a)
Scientific Report Institute Born-Bunge 2010. Page 38
12.
Bettens K, Brouwers N, Van Miegroet H, Gil A, Engelborghs S, De Deyn PP, Vandenberghe
R, Van Broeckhoven C, Sleegers K (2010a) Follow-up study of susceptibility loci for
Alzheimer's disease and onset age identified by genome-wide association. J Alzheimers Dis.
19(4):1169-75. (I.F. 2009: 3.832; cites: 3)
13.
Bettens K, Sleegers K, Van Broeckhoven C (2010b) Current status on Alzheimer disease
molecular genetics: from past, to present, to future. Hum Mol Genet., 19(R1):R4-R11. (I.F.
2009: 7.386; cites: 5)
14.
Bogaert E, Goris A, Van Damme,P., Geelen,V., Lemmens,R., van Es,M.A., van den Bergh,L.,
Sleegers,K., Verpoorten,N., Timmerman,V., De Jonghe,P., Van Broeckhoven,C.,
Traynor,B.J., Landers,J.E., Brown Jr.,R.H., Glass,J.D., Al-Chalabi,A., Shaw,C., Birve,A.,
Andersen,P.M., Slowik,A., Tomik,B., Melki,J., Robberecht,W., Van Den Bosch,L.:
Polymorphisms in the GluR2 gene are not associated with amyotrophic lateral sclerosis.
Neurobiology of Aging (2010) Epub: 19-Apr-2010 (I.F. 2009: 5.959; cites: 0)
15.
Brouns R, De Vil B, Cras P, De Surgeloose D, Mariën P, De Deyn PP (2010a)
Neurobiochemical Markers of Brain Damage in Cerebrospinal Fluid of Acute Ischemic Stroke
Patients. Clin Chem. 56(3):451-458. (I.F. 2009: 6.263; cites: 2)
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Rakocevic-Stojanovic V, Milic-Rasic V, Peric S, Baets J, Timmerman V, Dierick I,
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Harold,D., Hollingworth,P., Cellini,E., Takeda,M., Pericak-Vance,M., Younkin,S.,
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Rollinson S, Rohrer JD, van der Zee,J., Sleegers,K., Mead,S., Engelborghs,S., Collinge,J., De
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Van Dam D, Coen K, De Deyn P (2010) Ibuprofen modifies cognitive disease progression in
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Van Dam D, De Deyn PP. Invited review: Animal models in the drug discovery pipeline for
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Van Damme P, Philips T, Nguyen T, Weynants B, Vanacker,P., Dhondt,J., Sleegers,K.,
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102. Van Dijck A, Hayakawa E, Landuyt B, Baggerman G, Van Dam D, Luyten W, Schoofs L, De
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103. Van Dijck A, Van Dam D, De Deyn PP. Neuropeptides in Alzheimer's Disease: From
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104. Van Ginneken C, Schäfer KH, Van Dam D, Huygelen V, De Deyn PP (2011) Morphological
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105. Van Langenhove T, van der Zee J, Sleegers K, Engelborghs,S., Vandenberghe,R.,
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106. van West D, Del-Favero J, Deboutte D, Van Broeckhoven C, Claes S (2010) Associations
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107. Vanhoutte G , Verhoye M , Van Broeckhoven C, Kumar-Singh,S., Van Der Linden,A.: DTI
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108. Verheijen MHG, Hendriks WT, Peviani M, Smit AB, Bendotti C, Baas F, King RHM,
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ribosomes numbers is an early event in the pathogenesis of peripheral nerve disorders. PNS
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109. Vermeiren Y, Le Bastard N, Clarck C, Engelborghs S, De Deyn PP. Serum glutamine
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110. Weckhuysen S, Deprez L, Holmgren P, Suls A, Van Dyck T, Goossens D, Del-Favero,J.,
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111. Wikgren M, Karlsson T, Nilbrink T, Nordfjäll,K., Hultdin,J., Sleegers,K., Van
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112. Wils H, Janssens,J., Pereson,S., Kleinberger,G., Van Dam,D., Smits,V., Joris,G., Cuijt,I., De
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113. Wils H, Kleinberger G, Janssens J, Pereson S, Joris G, Cuijt I, Smits V, Ceuterick-de Groote
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115. Wostyn P, Audenaert K, De Deyn PP (2010a) Alzheimer's disease: cerebral glaucoma? Med
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117. Zhang F, Seeman P, Liu P, Weterman MAJ, Gonzaga-Jauregui,C., Towne,C.F., Batish,S.D.,
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119. Baets J, Dierick I, Ceuterick-de Groote C, Van Den Ende J.J, Martin J-J, Geens K,
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120. Baillieux H, Vandervliet EJ, Manto M, Parizel PM, De Deyn PP, Mariën P (2009)
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121. Bettens K, Brouwers N, Engelborghs S, De Pooter T, De Deyn PP, Sleegers K, Van
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disease: an update. Annals of Medicine 40: 562-583 (IF 4.246; cites: 25)
198. Ceulemans B, Storm K, Reyniers E, Callewaert L, Martin J-J (2008) Muscle pain as the only
presenting symptom in a girl with dystrophinopathy. Pediatr. Neurol., 38(1):64-66. (IF 1.497;
cites: 1)
199. Cruts,M., Van Broeckhoven,C. (2008): Loss of progranulin function in frontotemporal lobar
degeneration. Trends in Genetics 24(4): 186-194 (IF 8.659; cites: 22)
200. De Schutter E (2008) Reviewing multi-disciplinary papers: a challenge in neuroscience?
Neuroinformatics.;6(4):253-5. (IF 2.889; cites: 5)
Scientific Report Institute Born-Bunge 2010. Page 55
201. De Schutter E (2008) Why are computational neuroscience and systems biology so separate?
PLoS Comput Biol.;4(5):e1000078. (IF 5.895; cites: 9)
202. De Witte L, Engelborghs S, Verhoeven J, De Deyn PP, Mariën P (2008a) Disrupted autoactivation, dysexecutive and confabulating syndrome following bilateral thalamic and right
putaminal stroke. Behav Neurol., 19(3):145-51. (IF 1.308; cites: 0)
203. De Witte L, Verhoeven J, Engelborghs S, De Deyn PP, Mariën P (2008b) Crossed aphasia
and visuo-spatial neglect following a right thalamic stroke: a case study and review of the
literature. Behav Neurol., 19(4):177-94. (IF 1.308; cites: 0)
204. Deignan JL, Marescau B, Livesay JC, Iyer RK, De Deyn PP, Cederbaum SD, Grody WW
(2008) Increased plasma and tissue guanidino compounds in a mouse model of
hyperargininemia. Mol Genet Metab.;93(2):172-8. (IF 2.629; cites: 5)
205. Deprez,L., Weckhuysen,S., Peeters,K., Deconinck,T, Claeys,K., Claes,L., Suls,A., Van
Dyck,T., Palmini,A., Matthijs,G., Van Paesschen,W., De Jonghe,P. (2008): Epilepsy as part
of the phenotype associated with ATP1A2 mutations. Epilepsia 49(3): 500-508 (IF 3.733;
cites: 11)
206. Diener H.C., Sacco R.L., Yusuf S., Cotton D., et al. for the PRoFESS Study Group among
whom P.P. De Deyn (2008) Effects of aspirin plus extended-release dipyridamole versus
clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in
patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second
Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol.
7 (10): 875-884. (IF 14.270; cites: 24)
207. Dierckx E, Engelborghs S, De Raedt R, Van Buggenhout M, P.P. De Deyn, G. Verleye, D.
Verte, I. Ponjaert-Kristoffersen (2008). Differentiation between dementia and depression
among older persons: can the difference between actual and premorbid intelligence be useful?
J. Geriatr. Psychiatry Neurol. 21 (4): 242-249 (IF 1.794; cites: 1)
208. Dierick I, Baets J, Irobi J, Jacobs A, De Vriendt,E., Deconinck,T, Merlini,L., Van den
Bergh,P., Milic-Rasic,V., Robberecht,W., Fischer,D.F., Juntas Morales,R., Mitrovic,Z.,
Seeman,P., Mazanec,R., Kochañski,A., Jordanova,A., Auer-Grumbach,M., Helderman-van
den Enden,A.T.J.M., Wokke,J.J.H., Nelis,E., De Jonghe,P., Timmerman,V. (2008): Relative
contribution of mutations in genes for autosomal dominant distal hereditary motor
neuropathies: a genotype - phenotype correlation study. Brain 131(Pt 5): 1217-1227 (IF
9.603; cites: 13)
209. Engelborghs S, de Vreese K, van de Casteele T, Vanderstichele H, van Everbroeck B, Cras P,
Martin J-J, Vanmechelen E, de Deyn PP (2008a) Diagnostic performance of a CSF-biomarker
panel in autopsy-confirmed dementia. Neurobiol. Aging, 29(8): 1143-1159. (IF 5.969; cites:
25)
210. Engelborghs S, Vloeberghs E, Le Bastard N, Van Buggenhout M, Mariën P, Somers N,
Nagels G, Pickut BA, De Deyn PP (2008b) The dopaminergic neurotransmitter system is
associated with aggression and agitation in frontotemporal dementia. Neurochem Int.,
52(6):1052-60. (IF 3.228; cites: 8)
211. Errijgers V., E. Fransen, R. D’Hooge, P.P. De Deyn, R.F. Kooy (2008). Effect of genetic
background on acoustic startle response in fragile X knockout mice. Genet. Res. 90 (4): 341345 (IF 1.778; cites: 1)
212. Gallardo,E., Claeys,K.G., Nelis,E., García,A., Canga,A., Combarros,O., Timmerman,V., De
Jonghe,P., Berciano,J. (2008): Magnetic resonance imaging findings of leg musculature in
Charcot-Marie-Tooth disease type 2 due to dynamin 2 mutation. Journal of Neurology 255(7):
986-992 (IF 2.536; cites: 6)
Scientific Report Institute Born-Bunge 2010. Page 56
213. Gebruers N, Truijen S, Engelborghs S, Nagels G, Brouns R, De Deyn PP (2008) Actigraphic
measurement of motor deficits in acute ischemic stroke. Cerebrovasc Dis., 26(5):533-40. (IF
3.041; cites: 1)
214. Gijselinck I, Van Broeckhoven C, Cruts,M. (2008a): Granulin mutations associated with
frontotemporal lobar degeneration and related disorders: an update. Human Mutation 29(12):
1373-1386 (IF 7.033; cites: 19)
215. Gijselinck I, van der Zee J, S. Engelborghs, D. Goossens, K. Peeters, M. Mattheijssens, E.
Corsmit, J. Del-Favero, P.P. De Deyn, C. Van Broeckhoven, M. Cruts (2008b). Progranulin
locus deletion in frontotemporal dementia. Hum. Mutat. 29 (1): 53-58. (IF 7.033; cites: 25)
216. Haugarvoll K., R. Rademakers, J.M. Kachergus, K. Nuytemans, O.A. Ross, J.M Gibson, E.K.
Tan, C. Gaig, E. Tolosa, S. Goldwurm, M. Guidi, G. Riboldazzi, L. Brown, U. Walter, R.
Benecke, D. Berg, T. Gasser, J. Theuns, P. Pals, P. Cras, P.P. De Deyn, S. Engelborghs, B.
Pickut, R.J. Uitti, T. Foroud, W.C. Nichols, J. Hagenah, C. Klein, A. Samii, C.P. Zabetian, V.
Bonifati, C. Van Broeckhoven, M.J. Farrer, Z.K. Wszolek (2008). Lrrk2 R1441C
parkinsonism is clinically similar to sporadic Parkinson disease. Neurology 70 (16): 14561460 (IF 7.043; cites: 26)
217. Hong S, De Schutter E (2008) Purkinje neurons: What is the signal for complex spikes? Curr
Biol.;18(20):R969-71. (IF 2007: 10.539; cites: 1)
218. Hulshagen L., O. Krysko, A. Bottelbergs, S. Huyghe, R. Klein, P.P. Van Veldhoven, P.P. De
Deyn, R. D’Hooge, D. Hartman, M. Baes (2008). Absence of functional peroxisomes from
mouse CNS causes dysmyelination and axon degeneration. J. Neurosci. 28 (15): 4015-4027
(IF 7.452; cites: 11)
219. Kumar-Singh,S. (2008): Cerebral amyloid angiopathy: pathogenetic mechanisms and link to
dense amyloid plaques. Genes, Brain and Behavior 7(Suppl.1): 67-82 (IF 3.890; cites: 15)
220. Levillain O, Marescau B, Possemiers I, De Deyn PP (2008) Accumulation of
methylguanidine and changes in guanidino compound levels in plasma, urine, and kidneys of
furosemide-treated rats. Metabolism.;57(6):802-10. (IF 2.920; cites: 0)
221. Mariën P, Brouns R, Engelborghs S, Wackenier P, Verhoeven J, Ceulemans B, De Deyn PP
(2008) Cerebellar cognitive affective syndrome without global mental retardation in two
relatives with Gillespie syndrome. Cortex., 44(1):54-67. (IF 2.749; cites: 9)
222. Mayer S.A., N.C. Brun, K. Begtrup, J. Broderick, S. Davis, M.N. Diringer, B.E. Skolnick, T.
Steiner; FAST Trial Investigators among whom P.P. De Deyn (2008) Efficacy and safety of
recombinant activated factor VII for acute intracerebral hemorrhage. N. Engl. J. Med. 358
(20): 2127-37. (IF 50.017; cites: 141)
223. Monnier N, Marty I, Faure J, Castiglioni C, Desnuelle C, Sacconi S, Estournet B, Ferreiro A,
Romero N, Laquerrière A, Lazaro L, Martin J-J, Morava E, Rossi A, van der Kooi A, de
Visser M, Verschuuren C, Lunardi J (2008) Null mutations causing depletion of the type 1
ryanodine receptor (RYR1) are commonly associated with recessive structural congenital
myopathies with cores. Hum. Mutat., 29(5):670-678. (IF 7.033; cites: 12)
224. Nagels G., M.B. D’hooghe, D. Kos, S. Engelborghs, P.P. De Deyn (2008) Within-session
practice effect on paced auditory serial addition test in multiple sclerosis. Multiple Sclerosis
14: 106-111. (IF 3.312; cites: 1)
225. Nuytemans K , Pals P, Sleegers K, S. Engelborghs, E. Corsmit, K. Peeters, B. Pickut, M.
Mattheijssens, P. Cras, P.P. De Deyn, J. Theuns, C. Van Broeckhoven (2008a). Progranulin
variability has no major role in Parkinson disease genetic etiology. Neurology 71(15):1147-51
(IF 7.043; cites: 5)
Scientific Report Institute Born-Bunge 2010. Page 57
226. Nuytemans K., Rademakers R, Theuns J, P. Pals, S. Engelborghs, B. Pickut, T. de Pooter, K.
Peeters, M. Mattheijssens, M. Van den Broeck, P. Cras, P.P. De Deyn, C. Van Broeckhoven
(2008b). Founder mutation p.R1441C in the leucine-rich repeat kinase 2 gene in Belgian
Parkinson’s disease patients. Eur. J. Hum. Genet. 16 (4): 471-479. (IF 3.925; cites: 11)
227. Oertel W., W. Poewe, E. Wolters, P.P. De Deyn, M. Emre, C. Kirsch, C. Hsu, S. Tekin, R.
Lane (2008). Effects of rivastigmine on tremor and other motor symptoms in patients with
Parkinson’s disease dementia: a retrospective analysis of a double-blind trial and an openlabel extension. Drug Saf. 31 (1): 79-94. (IF 3.537; cites: 7)
228. Ramakers, I.H.G.B., Visser,P.J., Aalten,P., Bekers,O., Sleegers,K., Van Broeckhoven,C.,
Jolles,J., Verhey,F.R.J. (2008): The association between APOE genotype and memory
dysfunction in subjects with Mild Cognitive Impairment is related to age and Alzheimer
pathology. Dementia and Geriatric Cognitive Disorders 26(2): 101-108 (IF 3.142; cites: 10)
229. Reddel,S., Ouvrier,R., Nicholson,G., Dierick,I., Irobi,J., Timmerman,V., Ryan,M.M. (2008):
Autosomal dominant congenital spinal muscular atrophy: A possible developmental
deficiency of motor neurons? Neuromuscular Disorders 18(7): 530-535 (IF 2.932; cites: 2)
230. Sacco R.L., Diener H.C., Yusuf S., Cotton D; et al. for the PRoFESS Study Group among
whom P.P. De Deyn (2008) Aspirin and extended-release dipyridamole versus clopidogrel for
recurrent stroke. N. Engl. J. Med. 359 (12): 1238-1251. (IF 50.017; cites: 125)
231. Sleegers K, Kumar-Singh S, Cruts,M., Van Broeckhoven,C (2008) Molecular pathogenesis of
frontotemporal lobar degeneration. Archives of Neurology 65(6): 700-704 (2008) (I.F. 5.874;
cites: 1)
232. Stocchi F., Hersh B.P., Scott B.L., Nausieda P.A., Giorgi L. for the Ease-PD Monotherapy
Study Investigators among whom P.P. De Deyn (2008) Ropinirole 24-hour prolonged release
and ropinirole immediate release in early Parkinson’s disease: a randomized, double-blind,
non-inferiority crossover study. Curr. Med. Res. Opin. 24 (10): 2883-2895. (IF 2.596; cites:
12)
233. Suls A, Dedeken P, Goffin K, Van Esch H, Dupont P, Cassiman,D., Kempfle,J., Wuttke,T.V.,
Weber,Y., Lerche,H., Afawi,Z., Vandenberghe,W., Korczyn,A.D., Berkovic,S.F., Ekstein,D.,
Kivity,S., Ryvlin,P., Claes,L., Deprez,L., Maljevic,S., Vargas,A., Van Dyck,T., Goossens,D.,
Del-Favero,J., Van Laere,K., De Jonghe,P., Van Paesschen,W. (2008): Paroxysmal exerciseinduced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose
transporter, GLUT1. Brain 131(Pt 7): 1831-1844 (IF 9.603; cites: 34)
234. Taes YE, Marescau B, De Vriese A, De Deyn PP, Schepers E, Vanholder R, Delanghe JR
(2008) Guanidino compounds after creatine supplementation in renal failure patients and their
relation to inflammatory status. Nephrol Dial Transplant.; 23(4):1330-5. (IF 3.568; cites: 3)
235. Theuns,J., Van Broeckhoven,C. (2008): α-synuclein gene duplications in sporadic Parkinson
disease. Neurology 70(1): 7-9 (IF 7.043; cites: 2)
236. Van Broeck B, Vanhoutte G, Cuijt,I., Pereson,S., Joris,G., Timmermans,J-P., Van Der
Linden,A., Van Broeckhoven,C., Kumar-Singh,S. (2008a): Reduced brain volumes in mice
expressing APP-Austrian mutation but not in mice expressing APP-Swedish-Austrian
mutations. Neuroscience Letters 447: 143-147 (IF 2.200; cites: 0)
237. Van Broeck B, Vanhoutte G, Pirici D, D. Van Dam, H. Wils, I. Cuijt, K. Vennekens, M.
Zabielski, A. Michalik, J. Theuns, P.P. De Deyn, A. Van der Linden, C. Van Broeckhoven, S.
Kumar-Singh (2008b). Intraneuronal amyloidβ and reduced brain volume in a novel
APPT7141 mouse model for Alzheimer’s disease. Neurobiol. Aging 29: 241-252. (IF 5.969;
cites: 12)
Scientific Report Institute Born-Bunge 2010. Page 58
238. Van Dam D, Coen K, De Deyn PP (2008) Cognitive evaluation of disease-modifying efficacy
of donepezil in the APP23 mouse model for Alzheimer's disease. Psychopharmacology
(Berl).;197(1):37-43. (IF 3.676; cites: 7)
239. van der Zee J, Sleegers K , Van Broeckhoven C (2008a): Invited article: the Alzheimer's
disease - frontotemporal lobar degeneration spectrum. Neurology 71: 1191-1197 (IF 7.043;
cites: 11)
240. van der Zee J, Urwin H, Engelborghs S, Bruyland M, R. Vandenberghe, B. Dermaut, T. De
Pooter, K. Peeters, P. Santens, P.P. De Deyn, E.M. Fisher, J. Collinge, A.M. Isaacs, C. Van
Broeckhoven (2008b) CHMP2B C-truncating mutations in frontotemporal lobar degeneration
are associate with an aberrant endosomal phenotype in vitro. Hum. Mol. Genet. 17 (2): 313322. (IF 7.249; cites: 16)
241. Van Diest D, De Raeve H, Claes J, Parizel PM, De Ridder D, Cras P (2008) Paraneoplastic
Opsoclonus-Myoclonus-Ataxia (OMA) syndrome in an adult patient with
esthesioneuroblastoma. J Neurol. 255(4):594-6. (IF 2.536; cites: 1)
242. Van Dijck A, Vloeberghs E, Van Dam D, Staufenbiel M, De Deyn PP (2008) Evaluation of
the APP23-model for Alzheimer's disease in the odour paired-associate test for hippocampusdependent memory. Behav Brain Res.;190(1):147-51. (IF 3.171; cites: 2)
243. Van Geit W, De Schutter E, Achard P (2008) Automated neuron model optimization
techniques: a review. Biol Cybern.;99(4-5):241-51. (IF 1.935; cites: 7)
244. Vandervliet EJ, Verhoeven J, Engelborghs S, De Deyn PP, Parizel PM, Mariën P (2008)
FMRI findings in an aphasic patient with reversed cerebral dominance for language. Acta
Neurol Belg., 108(4):161-6. (IF 0.770; cites: 0)
245. Vanholder R., Baurmeister U., Brunet P., G. Cohen, G. Glorieux, J. Jankowski, for the
European Uremic Toxin Work Group among whom P.P. De Deyn (2008a) A bench to bedside
view of uremic toxins. J. Am. Soc. Nephrol. 19 (5): 863-870. (IF 7.505; cites: 20)
246. Vanholder R., De Deyn P.P., W. Van Biesen, N. Lameire (2008b). Marconi revisited: From
kidney to brain – Two organ systems communicating at long distance. J. Am. Soc. Nephrol.
19 (7): 1253-1255 (IF 7.505; cites: 4)
247. Visser P.J., F.R. Verhey, M. Boada, R. Bullock, P.P. De Deyn, G.B. Frisoni, L. Frolich, H.
Hampel, J. Jolles, R. Jones, L. Minthon, F. Nobili, M. Olde Rikkert, P.J. Ousset, A.S. Rigaud,
P. Scheltens, H. Soininen, L. Spiru, J. Touchon, M. Tsolaki, B. Vellas, L.O. Wahlund, G.
Wilcock, B. Winblad; DESCRIPA study group (2008) Development of screening guidelines
and clinical criteria for predementia Alzheimer’s disease. The DESCRIPA Study.
Neuroepidemiology 30 (4): 254-265. (IF 1.737; cites: 7)
248. Vloeberghs E, Coen K, Van Dam D, De Deyn PP (2008a) Validation of the APP23 transgenic
mouse model of Alzheimer's disease through evaluation of risperidone treatment on
aggressive behaviour. Arzneimittelforschung.;58(6):265-8. (IF 0.713; cites: 2)
249. Vloeberghs E, Van Dam D, Franck F, Serroyen J, Geert M, Staufenbiel M, De Deyn PP
(2008b) Altered ingestive behavior, weight changes, and intact olfactory sense in an APP
overexpression model. Behav Neurosci.;122(3):491-7. (IF 2.596; cites: 4)
250. Willemse JL, Brouns R, Heylen E, De Deyn PP, Hendriks DF (2008) Carboxypeptidase U
(TAFIa) activity is induced in vivo in ischemic stroke patients receiving thrombolytic therapy.
J Thromb Haemost. 2008 Jan;6(1):200-2. (IF 6.291; cites: 6)
251. Winblad B., S. Gauthier, L. Scinto, H. Feldman, G.K. Wilcock, L. Truyen, A.J. Mayorga, W.
Wang, H.R. Brashear, J.S. Nye; GAL-INT-11/18 Study Group among whom P.P. De Deyn
Scientific Report Institute Born-Bunge 2010. Page 59
(2008) Safety and efficacy of galantamine in subjects with mild cognitive impairment.
Neurology 70 (22): 2024-35. (IF 7.043; cites: 36)
252. Wostyn P, Audenaert K, De Deyn PP (2008a) Alzheimer’s disease-related changes in diseases
characterized by elevation of intracranial or intraocular pressure. Clin. Neurol. Neurosurg.
110 (2): 101-109. (IF 1.323; cites: 6)
253. Wostyn P, Audenaert K, De Deyn PP (2008b) An abnormal high trans-lamina cribrosa
pressure difference: a missing link between Alzheimer’s disease and glaucoma? Clin. Neurol.
Neurosurg. 110 (7): 753-754 (IF 1.323; cites: 0)
254. Yusuf S, Diener HC, Sacco R.L., Cotton D., et al. for the PRoFESS Study Group among
whom P.P. De Deyn (2008) Telmisartan to prevent recurrent stroke and cardiovascular events.
N. Engl. J. Med. 359 (12): 1225-1237. (IF 50.017; cites: 143)
a2 – papers in scientific journals review by international experts
1.
Azdad K, Chàvez M, Don Bischop P, Wetzelaer P, Marescau B, De Deyn PP, Gall D,
Schiffman SN (2009) Homeostatic plasticity of striatal neurons intrinsic excitability following
dopamine depletion. PLoS one 4 (9): e6908.
2.
Dintchov Traykov L, Mehrabian S, Van den Broeck M, Radoslavova Raycheva M, Cruts M,
Kirilova Jordanova A, Van Broeckhoven C (2009) Novel PSEN1 mutation in a Bulgarian
patient with very early-onset Alzheimer’s disease, spastic paraparesis and extrapyramidal
signs. Am J Alzheimers Dis Other Demen. 24: 404-7.
3.
Le Bastard N, De Deyn PP, Engelborghs S (2009) Cerebrospinal fluid biomarkers for the
differential diagnosis of dementia. CML-Neurology. 25:59-68.
4.
Roels F, Verloo P, Eyskens F, François B, Seneca S, De Paepe B, Martin JJ, Meersschaut V,
Praet M, Scalais E, Espeel M, Smet J, Van Goethem G, Van Coster R (2009) Mitochondrial
mosaics in the liver of 3 infants with mtDNA defect. BMC Clin Pathol. 9:4.
5.
van Bogaert P.P (2010) Heart rate reducing drugs: mechanisms of action. Current topics in
Pharmacology 78:120-33.
6.
Wils S, De Schutter E (2009) STEPS: Modeling and Simulating Complex Reaction-Diffusion
Systems with Python. Front Neuroinformatics. 3:15. (no ISI I.F.)
7.
Wostyn P, Audenaert K, De Deyn PP (2009b) More advanced Alzheimer's disease may be
associated with a decrease in cerebrospinal fluid pressure. Cerebrospinal Fluid Res. 6:14. (no
ISI I.F.)
8.
Achard P, De Schutter E (2008) Calcium, synaptic plasticity and intrinsic homeostasis in
purkinje neuron models. Front Comput Neurosci.;2:8.
a3 – papers in nationale journals with reading committee
1.
Crosiers D, Ceulemans,B., Meeus,B., Corsmit,E., Pals,P., Van Broeckhoven,C., Cras,P.,
Theuns,J.: Een zeldzame genetische oorzaak voor juveniel parkinsonisme en dementie.
Lentevergadering Vereniging voor Vlaamse Neurologen, Leuven, Belgium, March 27 :
(2010)
2.
Crosiers D, Nuytemans K, Meeus B, Theuns J, Van Broeckhoven C, Cras P .: Korte screening
voor niet-motorische symptomen bij de ziekte van Parkinson. Tijdschrift voor Neurologie &
Neurochirurgie 111: 113-117 (2010)
Scientific Report Institute Born-Bunge 2010. Page 60
3.
De Ryck A, Brouns R, Geurden M, Elseviers M, De Deyn PP, Engelborghs S (2009)
Risicofactoren voor depressie na CVA. Een systematische literatuurstudie. Tijdschrift voor
Geneeskunde. 65: 282-90.
a4 – papers not included in a1, a2 or a3
b1 – author or co-author of books
b2 – chapters in books
1.
Baets,J., Hanemann,C., De Jonghe,P.: Inherited Peripheral Neuropathies. In: Encyclopedia of
Molecular Mechanisms of Diseases Edited by Lang, Florian (Springer): (2010)
2.
Boustany R-M, Ceuterick-de Groote C, Goebel HH, Martin J-J, Mole S, and Schulz A. Chapter
14; Genetically unassigned or unusual NCLs in “The Neuronal Ceroid lipofuscinoses (Batten
disease)”. Second Edition. Edited SE Mole, R Williams, and HH Goebel. Oxford university
Press; Feb 2011
3.
Ceuterick-de Groote C, Mole S, Goebel HH, Martin J-J. Chapter section on Adult onset-CLN4,
Chapter 10 NCL without genetic assignment in 2nd edition of “The neuronal ceroid
lipofuscinoses (Batten disease)”. IOS Press Book. SE Mole, HH Goebel, R Williams (eds).
4.
De Deyn, PP & Van Dam, D (2010). General introduction to animal models of human
conditions. Eds. De Deyn, PP & Van Dam, D. Springer Science + Business Media: New York.
5.
De Deyn, PP & Van Dam, D (2010). Dementia. In: Encyclopedia of Psychopharmacology.
Stolerman, Ian P. (Ed.) Springer; 1st Edition.
6.
Engelborghs S., P. Mariën, P.P. De Deyn. Frontal lobe dysfunction across diagnostic dementia
categories. In: Neuropsychology in progress. P. Mariën, J. Abutalebi (Eds.). London:
Psychology Press, in press.
7.
Landrieu,P., Baets,J., De Jonghe,P.: Hereditary motor-sensory, motor and sensory neuropathies
in childhood. In: Pediatric neurology handbook of clinical neurology (In Press)
8.
Pirici D, Van Broeckhoven C, Kumar-Singh S (2010) Alzheimer’s disease mouse models and
their relevance to human disease. Eds. De Deyn, PP & Van Dam, D. Springer Science +
Business Media: New York.
9.
Sleegers,K., Van Broeckhoven,C.: Frontotemporal dementia. In: Brocklehurst Textbook of
Gerontology and Geriatric Medicine - 7th edition (Elsevier): (2010)
10. Van Dam, D & De Deyn, PP (2010). The APP23 mouse model for Alzheimer’s disease. In
Animal models of dementia. Eds. De Deyn, PP & Van Dam, D. Springer Science + Business
Media: New York.
11. Van Dam, D & De Deyn, PP (2010). The role of rodent models in the drug discovery pipeline
for dementia. Eds. De Deyn, PP & Van Dam, D. Springer Science + Business Media: New
York.
12. Van Dam, D, Van Dijck A, & De Deyn, PP (2010). Behavioral validation in animal models of
dementia. Eds. De Deyn, PP & Van Dam, D. Springer Science + Business Media: New York.
13. Van Dijck A, Van Dam, D & De Deyn, PP (2010). Species, strain and gender issues. Eds. De
Deyn, PP & Van Dam, D. Springer Science + Business Media: New York.
B3 – Edited Books
Scientific Report Institute Born-Bunge 2010. Page 61
De Deyn P.P., Van Dam D. (Eds) Animal models of Dementia. Neuromethods series; Humana
Press / Springer. December 2010.
c1 – papers in Proceedings of Scientific Meetings
c2 – Dissertations, theses, internal reports, abstracts of presentations/posters at congresses
Dissertations Professional Bachelors:
Brys Jolien
Mutatiescreening van het microtubuli geassocieerde proteïne tau (MAPT) en progranuline gen
(PGRN) in Alzheimer en frontotemporale dementie patiënten.
Promotoren: C. Van Broeckhoven, Co-promotor: J. van der Zee
Coolman Sofie
Gedragsmatige validatie van het transgene APP23-muismodel voor de ziekte van Alzheimer.
Promotoren: P.P. De Deyn, Co-promotor: D. Van Dam
De Ren Jan
Onderzoek naar genetische factoren voor frontotemporale kwabdegeneratie aan de hand van
mutatie-analyse van functionele kandidaatgenen
Promotor: M. Cruts
De Ryck Jolien
DNA diagnostiek voor de ziekte van Charcot-Marie-Tooth type 1: van klinische diagnose tot
mutatie.
Promotoren: C. Van Broeckhoven
Eysackers Nathalie
Identificatie en karakterisatie van mutaties in genen voor Alzheimer dementie
Promotor: K. Sleegers
Goudman Tom
Analyse van biogene amines uit hersenweefsel door middel van HPLC met elektrochemische
detectie.
Promotor: P.P. De Deyn; Co-promotor: D. Van Dam
Peeters Kristien
Fijnmappen van de locus voor de ziekte van Charcot-Marie-Tooth type 2G.
Promotoren: V. Timmerman
Roberts Josephine
Mutatieanalyse van PRX bij vroeg beginnende vormen van de ziekte van Charcot-Marie-Tooth
Promotor: A. Jordanova
Quisenaerts Iris
Evaluatie van QC-Plex. Optimalisatie van Progranuline-MAQ
Promotor: D. Goossens
Verstraeten Aline
Mutatieanalyse van kandidaatgenen voor ‘Lewy Body’ hersenziekte gekoppeld aan chromosoom 2.
Promotoren: J. Theuns
Scientific Report Institute Born-Bunge 2010. Page 62
Waumans Yannick
Moleculaire karakterisatie van dominant intermediaire vorm van de ziekte van Charcot-MarieTooth type D: op zoek naar een gemeenschappelijke voorouder.
Promotoren: A. Jordanova
Lotte Van Hoeck
Mutatieanalyse van het optineurine gen in amyotrofische laterale sclerose patiënten en van het
microtubule-associated proteint au gen in frontaalkwabdementie patiënten.
Promotoren: KdG – IWT, Campus Hoboken & T. Van Langenhove
Gregori Vingerhoets
Identificatie en karakterisatie van mutaties in genen voor Alzheimer dementie
Promotoren: KdG – IWT, Campus Hoboken & N. Brouwers
Tinne Schellekens
Opsporen van het genetisch defect in een nieuwe locus voor frontotemporale kwab degeneratie en
amyotrofe laterale sclerose.
Promotor: Plantijn Hogeschool & I. Gijselinck
Master’s theses
Busseniers Jonas
Investigation of apoptosis in progranulin knockdown cell models
Promotoren: C. Van Broeckhoven & G. Kleinberger
De Clerck Ben
Optimalisatie van de Proximity Ligation Assay (PLA) methode als uitleessysteem voor TLR
activering
Promotor: S. Janssens
Dondelinger Yves
Zoektocht naar nieuwe pathomechanismen voor CMT-geassocieerde HSPB1 en HSPB8 mutanten
Promotor: S. Janssens
Fredrickx Evelien
Characterisation of the Mtmr2/Fig4 double knockout mouse model
Promotors: Vincent Timmerman & Alessandra Bolino
Hardies Katia
Moleculair genetische analyse van X-gebonden en recessieve epilepsieën
Promotor: Peter De Jonghe
Holmgren Philip
Moleculair genetische analyse van vroegtijdige epilepsieën
Promotoren: A. Jordanova & P. De Jonghe
Janssens Jonathan
Biochemische en neuropathologische karakterisering van een nieuw human TDP-43 overexpressing
muismodel
Promotor: S. Kumar-Singh
Janssen Leen
Scientific Report Institute Born-Bunge 2010. Page 63
Evaluatie van ziektemodulerende effecten van overmatige ethanolconsumptie in het transgene
APP23 muismodel voor de ziekte van Alzheimer.
Promotor: P.P. De Deyn; Co-promotor: D. Van Dam
Peeters Kristien
Genetische koppelingsanalyse en identifivatie van nieuwe FLNC mutaties in families met distale
myopathie
Promotors: Albena Jordanova & Peter De Jonghe
Philtjens Stéphanie
Pathway-based genetic analyses to detect novel genes associated with frontotemporal lobar
degeneration
Promotoren: P. Stinissen & M. Cruts
Sales Carbonell Carola
Behavioural phenotyping of a transgenic mouse model of Alzheimer’s disease: sleep and circadian
rhythms.
Promotor: P.P. De Deyn; Co-promotor: D. Van Dam
Slaets Sylvia
Karakteristieken van de ziekte van Alzheimer in neuropathologisch geconfirmeerde dementie met
Lewy bodies
Promotoren: P.P. De Deyn; S. Engelborghs
Smits Veerle
Expressie van Nod-like receptors in het perifere en het centrale zenuwstelsel
Promotor: S. Janssens
Van Avondt Kristof
De rol van de aangeboren immuunrespons in acute perifere neuropathieën.
Promotor: S. Janssens
Van Cauwenberghe Caroline
Inleiding tot immunocytochemie en western blotting technieken voor FTLD
Promotor: S. Kumar-Singh
Vanbeginne Stéphanie
Characterization and identification of granulin missense mutations in patients with Alzheimer
dementia
Promotoren: K. Sleegers & N. Brouwers
Van Hoorenbeeck Kim en Yperzeele Laetitia
Het klinisch spectrum van erfelijke polyneuropathieën.
Promotor: P. De Jonghe
Van Langenhove Tim
Genetic analysis fo the valosin containing protien gene in Belgian frontotemporal lobar
degeneration patients and clinico-pathological characterization of mutation carriers.
Promotor: C. Van Broeckhoven, Co-promotor: J. van der Zee
Van Rossom Sofie
Scientific Report Institute Born-Bunge 2010. Page 64
Neurochemische correlaten van mannelijk aggressief gedrag in het transgene APP23 muismodel
voor de ziekte van Alzheimer.
Promotor: P.P. De Deyn; Co-promotor: D. Van Dam
Verelst Quinten
Mutatie-analyse van genen voor CMT: GDAP1 en SETX.
Promotor: I. Dierick
Verelst Quinten
Opsporen van het genetisch defect in een locus voor frontotemporale kwabdegeneratie
Promotoren: Marc Cruts & Ilse Gijselinck
Vermeiren Yannick
Gedragscorrelaten van melatonine in serum bij dementie
Promotoren: P.P. De Deyn; S. Engelborghs
Vervoort Jasha
Effect van DI-CMTC mutaties in YARS op celgroei en eiwitinteracties
Promotoren: A. Jordanova & V. Timmerman
Abstracts
2010
1.
Baets,J., Zimon,M., De Vriendt,E., Deconinck,T, Spiegel,R., Parman,Y., Ceulemans,B.,
Vilain,C., Pou-Serradell,A., Bernert,G., Dinopoulos,A., Auer-Grumbach,M., Sallinen,S.-L.,
Fabrizi,G.-M., Pauly,F., Van den Bergh,P., Battaloglu,E., Madrid,R., Timmerman,V.,
Jordanova,A., De Jonghe,P.: Genetic spectrum of hereditary peripheral neuropathies with onset
in the first year of life Peripheral Nerve Society Satellite Meeting, Sydney, Australia, July 5-7 :
(2010)
2.
Bettens,K., Brouwers,N., Gil,A., Van Miegroet,H., Engelborghs,S., De Deyn,P.P.,
Vandenberghe,R., Sleegers,K., Van Broeckhoven,C.: In-depth molecular genetic analysis of
CLU in Alzheimer's disease. Alzheimer's Association International Conference on Alzheimer's
Disease 2010 (ICAD 2010), July 10-15 : (2010)
3.
Brouwers,N., Van Cauwenberghe,C., Bettens,K., Engelborghs,S., Van Miegroet,H., Gil
Montoya,A., Peeters,K., Mattheijssens,M., Vandenberghe,R., De Deyn,P.P., Cruts,M.,
Sleegers,K., Van Broeckhoven,C.: Complement receptor 1 variability is associated with
increased risk for Alzheimer's disease in an extended Flemish-Belgian population. Human
Genome Meeting - HGM 2010, Montpellier, France, May 18-21 : (2010)
4. Crosiers, D., Meeus, B., Nuytemans, K., Van Broeckhoven, C., Theuns, J., and Cras, P., Selfreported non-motor symptoms in a cohort of 139 Parkinson's disease patients. Movement
Disorders 25 (S3): S655 (2010)
5. Crosiers, D., Ceulemans, B., Meeus, B., Nuytemans, K., Corsmit, E., Van den Broeck, M., Pals,
P., Van Broeckhoven, C., Cras, P., and Theuns, J.. Movement Disorders 25 (7): S470 (2010)
6.
Crosiers,D., Ceulemans,B., Meeus,B., Nuytemans,K., Corsmit,E., Van den Broeck,M., Pals,P.,
Van Broeckhoven,C., Cras,P., Theuns,J.: Juvenile parkinsonism and dementia: a novel
ATP13A2 frameshift mutation. VIB Seminar 2010, Blankenberge, Belgium, March 4 : P80
(2010)
Scientific Report Institute Born-Bunge 2010. Page 65
7.
de almeida Souza,L., Goethals,S., De Winter,V., Dierick,I., Gallardo,E., Van Durme,J., Irobi,J.,
Gettemans,J., Rousseau,F., Schymkowitz,J., Timmerman,V., Janssens,S.: Increased
monomerization of mutant HSPB1 leads to protein hyperactivity in CMT neuropathy. VIB
Seminar 2010, Blankenberge, Belgium, March 4 : Oral Talk 13 (2010)
8.
De Deyn P.P. Treatment of behavioural and psychological symptoms of dementia: which
strategies? The 8th Summer School of Neuroscience: “Schizophrenia and other psychosis: what
can clinics learn from basic sciences?” Abstract book p. 100 (2010)
9.
Garbern,J.Y., Nicholson,G.A., Kowalski,B., Chu,S., Takata,R., Speck-Martins,C., Baets,J.,
Almeida-Souza,L., Fischer,D., Timmerman,V., Kaler,S.G., Bird,T.D., De Jonghe,P.,
Lewis,R.A., Feely,S.M.E., Shy,M.E., Ferguson,T., Scherer,S.S., Kennerson,M.L.: Upper as
well as lower motor neuronal phenotypes associated with mutation affecting the coppertransporter ATP7A Peripheral Nerve Society Satellite Meeting, Sydney, Australia, July 5-7 :
(2010)
10. Gijselinck,I., Engelborghs,S., Maes,G., Cuijt,I., Ben-Azza,J., Bäumer,V., Peeters,K.,
Mattheijssens,M., Joris,G., Cras,P., Martin,J-J., De Deyn,P.P., Kumar-Singh,S., Van
Broeckhoven,C., Cruts,M.: Genomic study of the chromosome 9 locus linked with FTLD and
ALS. Human Genome Meeting - HGM 2010, Montpellier, France, May 18-21 : (2010)
11. Holmgren,A., De Winter,V., Asselbergh,B., Timmerman,V., Irobi,J.: Overexpression of mutant
HSPB1 and HSPB8 in intermediate filament negative SW13 cells could alter neurofilament
network. VIB Seminar 2010, Blankenberge, Belgium, March 4 : P68 (2010)
12. Kennerson,M.L., Nicholson,G., Kaler,S.G., Kowalski,B., Mercer,J.F.B., Tang,J., Llanos,R.M.,
Chu,S., Takata,R.I., Speck-Martins,C.E., Baets,J., Almeida-Souza,L., Fischer,D.,
Timmerman,V., Taylor,P.E., Scherer,S.S., Ferguson,T.E., Bird,T.D., De Jonghe,P.,
Feely,S.M.E., Shy,M.E., Garbern,J.Y.: Discovery of mutation in the copper transporter gene
ATP7A causing X-linked distal hereditary motor neuropathy Peripheral Nerve Society Satellite
Meeting, Sydney, Australia, July 5-7 : (2010)
13. Kleinberger,G., Wils,H., Ponsaerts,P., Joris,G., Timmermans,J-P., Van Broeckhoven,C.,
Kumar-Singh,S.: Increased caspase activation and decreased TDP-43 solubility in progranulin
knockout cortical cultures. VIB Seminar 2010, Blankenberge, Belgium, March 4 : P69 (2010)
14. Meeus, B., Verstraeten, A., Nuytemans, K., Crosiers, D., Engelborghs, S., Van den Broeck, M.,
Brys, J., Mattheijssens, M., Peeters, K., Corsmit, E., Elinck, E., Pickut, B., Cras, P.,
Vandenberghe, R., De Deyn, PP, Van Broeckhoven, C., and Theuns, J. Dementia with Lewy
bodies: a role for mutations in dementia and Parkinson's disease genes? Movement Disorders
25 (S3): S614 (2010)
15. Meeus, B., Verstraeten, A., Nuytemans, K., Crosiers, D., Engelborghs, S., Van den Broeck, M.,
Brys, J., Mattheijssens, M., Peeters, K., Corsmit, E., Elinck, E., Pickut, B., Cras, P.,
Vandenberghe, R., De Deyn, PP, Van Broeckhoven, C., and Theuns, J. Dementia with Lewy
bodies: a role for mutations in dementia and Parkinson's disease genes? Annual Scientific
IAP6/43 meeting, University of Leuven, October 25 (2010)
16. Reitz,C., Cheng,R., Rogaeva,E., Lee,J., Tokuhiro,S., Bettens,K., Sleegers,K., King Tan,E.,
Kimura,R., Shibata,N., Kamboh,M.I., Prince,J., Maier,W., Riemenschneider,M., Owen,M.,
Harold,D., Hollingworth,P., Cellini,E., Pericak-Vance,M.A., Younkin,S., Williams,J., Van
Broeckhoven,C., Farrer,L.A., St. George-Hyslop,P., Mayeux,R.: Meta-analysis of the
association between SORL1 variants and Alzheimer's disease. Alzheimer's Association
International Conference on Alzheimer's Disease 2010 (ICAD 2010), July 10-15 : (2010)
Scientific Report Institute Born-Bunge 2010. Page 66
17. van der Zee,J., Van Langenhove,T., Kleinberger,G., Sleegers,K., Engelborghs,S.,
Vandenberghe,R., Santens,P., Cras,P., De Deyn,P.P., Cruts,M., Van Broeckhoven,C.:
TMEM106B The first common risk factor for FTLD: replication in a clinically diagnosed
cohort of FTLD patients. Alzheimer's Association International Conference on Alzheimer's
Disease 2010 (ICAD 2010), July 10-15 : (2010)
18. Van Langenhove,T., van der Zee,J., Sleegers,K., Engelborghs,S., Vandenberghe,R.,
Gijselinck,I., Van den Broeck,M., Mattheijssens,M., Peeters,K., De Deyn,P., Cruts,M., Van
Broeckhoven,C.: Genetic contribution of FUS to frontotemporal lobar degeneration. VIB
Seminar 2010, Blankenberge, Belgium, March 4 : P91 (2010)
19. Zimon,M., Baets,J., Auer-Grumbach,M., Berciano,J., Garcia,A., Lopez-Laso,E., Merlini,L.,
Hilton-Jones,D., McEntagart,M., Crosby,A., Barisic,N., Boltshauser,E., Shaw,C.E.,
Landouré,G., Ludlow,C.L., Gaudet,R., Houlden,H., Reilly,M.M., Fischbeck,K.H., Sumner,C.J.,
Timmerman,V., Jordanova,A., De Jonghe,P.: Dominant mutations in the cation channel gene
TRP4 cause an unusual spectrum of neuropathies Peripheral Nerve Society Satellite Meeting,
Sydney, Australia, July 5-7 : (2010)
20. Zimon,M., Baets,J., Auer-Grumbach,M., Berciano,J., Lopez-Laso,E., Merlini,L., HiltonJones,D., McEntagart,M., Crosby,A.H., Barisic,N., Boltshauser,E., Landouré,G., Ludlow,C.L.,
Gaudet,R., Houlden,H., Reilly,M., Fischbeck,K., Sumner,C.J., Timmerman,V., Jordanova,A.,
De Jonghe,P.: Dominant mutations in the cation channel gene TRPV4 cause an unusual
spectrum of neuropathies. VIB Seminar 2010, Blankenberge, Belgium, March 4 : Oral Talk 15
(2010)
21. Zimon,M., Baets,J., Auer-Grumbach,M., Berciano,J., Merlini,L., Hilton-Jones,D.,
McEntagart,M., Crosby,A.H., Barisic,N., Bolsthauser,E., Landouré,G., Ludlow,C.L.,
Gaudet,R., Houlden,H., Reilly,M., Fischbeck,K., Sumner,C.J., Timmerman,V., Jordanova,A.,
De Jonghe,P.: Dominant mutations in the cation channel gene TRPV4 cause an unusual
spectrum of neuropathies. 10th Annual Meeting of the Belgian Society of Human Genetics,
Belgium, Gent, February 26 : P78 (2010)
22. Le Bastard N., De Deyn P.P., Engelborghs S. Plasma beta-amyloid levels: diagnostic marker
for dementia diagnosis? Alzheimer’s and Dementia 6 (Suppl. 1): S519 (2010) Alzheimer's
Association International Conference on Alzheimer's Disease 2010 (ICAD 2010), July 10-15 :
(2010)
23. Le Bastard N., De Deyn P.P., Engelborghs S. Standardization of CSF sampling to minimize
variation in CSF biomarker levels. Alzheimer’s and Dementia 6 (Suppl. 1): S522 (2010)
Alzheimer's Association International Conference on Alzheimer's Disease 2010 (ICAD 2010),
July 10-15 : (2010)
24. Le Bastard N., De Deyn P.P., Engelborghs S. Longitudinal stability of CSF biomarker levels.
Alzheimer’s and Dementia 6 (Suppl. 1): S528 (2010) Alzheimer's Association International
Conference on Alzheimer's Disease 2010 (ICAD 2010), July 10-15 : (2010)
25. Dierckx E., Engelborghs S., De Raedt R., Van Buggenhout M., De Deyn P.P., PonjaertKristoffersen I. Predicting conversion to Alzheimer’s disease in mild cognitive impairment:
cued recall versus free delayed recall. Alzheimer’s and Dementia 6 (Suppl. 1): S357 (2010)
Alzheimer's Association International Conference on Alzheimer's Disease 2010 (ICAD 2010),
July 10-15 : (2010)
2009
26. Baets,J., Deconinck,T, Smouts,I., Goossens,D., Van Den Berg,P., Schmedding,E., Santens,P.,
Milic-Rasic,V., Van Damme,P., Robberecht,W., De Meirleir,L., Jordanova,A., De Jonghe,P.:
ARSACS in patients initially referred as CMT. Third International Charcot-Marie-Tooth
Consortium Meeting, Antwerp, Belgium, July 9-11 : P29 (2009)
Scientific Report Institute Born-Bunge 2010. Page 67
27. Baets,J., Zimon,M., De Vriendt,E., Deconinck,T, Battaloglu,E., Spiegel,R., Parman,Y.,
Jordanova,A., De Jonghe,P.: Genetic spectrum of hereditary peripheral neuropathies with onset
in the first year of life. Third International Charcot-Marie-Tooth Consortium Meeting,
Antwerp, Belgium, July 9-11 : P28 (2009)
28. Baets,J., Zimon,M., De Vriendt,E., Deconinck,T, Battaloglu,E., Spiegel,R., Parman,Y.,
Jordanova,A., De Jonghe,P.: Genetic spectrum of hereditary peripheral neuropathies with onset
in the first year of life. Annual Scientific IAP6/43 meeting, University of Brussels (ULB),
October 26 : 17 (2009)
29. Berciano,J., García,A., Gallardo,E., Ramón,C., Maraví,E., Infante,J., Gastón,I., Alonso,A.,
Combarros,O., De Jonghe,P.: CMT2J disease with MPZ Thr124Met mutation: Clinicoelectrophysiological and MRI study of a family. Third International Charcot-Marie-Tooth
Consortium Meeting, Antwerp, Belgium, July 9-11 : P25 (2009)
30. Bettens,K., Brouwers,N., Engelborghs,S., Van Miegroet,H., De Deyn,P., Theuns,J.,
Sleegers,K., Van Broeckhoven,C.: miRNA genetic variability of APP and BACE1 has no
major role in risk for Alzheimer?s disease. Annual Scientific IAP6/43 meeting, University of
Brussels (ULB), October 26 : 18 (2009)
31. Brouwers,N., Bettens,K., Gijselinck,I., Engelborghs,S., Pickut,B., Van Miegroet,H., Gil
Montoya,A., Mattheijssens,M., Peeters,K., De Deyn,P., Cruts,M., Sleegers,K., Van
Broeckhoven,C.: Contribution of TARDBP to Alzheimer Disease genetic etiology. Annual
Scientific IAP6/43 meeting, University of Brussels (ULB), October 26 : 20 (2009)
32. Cavallaro,T., Ferrarini,M., Taioli,F., Zimon,M., De Jonghe,P., Jordanova,A., Fabrizi,G.-M.:
Autosomal dominant Charcot-Marie-Tooth disease type 2 associated with Ganglioside-induced
differentiation-associated protein 1 gene. Third International Charcot-Marie-Tooth Consortium
Meeting, Antwerp, Belgium, July 9-11 : P45 (2009)
33. Crosiers,D., Ceulemans,B., Meeus,B., Corsmit,E., Van Broeckhoven,C., Cras,P., Theuns,J.: A
novel ATP13A2 frameshift mutation leading to Kufor-Rakeb syndrome. Annual Scientific
IAP6/43 meeting, University of Brussels (ULB), October 26 : 21 (2009)
34. Crosiers,D., Meeus,B., Ceulemans,B., Van Broeckhoven,C., Cras,P., Theuns,J.: Juvenile
parkinsonism caused by a novel ATP13A2 frameshift mutation. Genetic epidemiology of
Parkinson's Disease 4th Annual Meeting (GEO-PD), Tübingen, Germany July 6-8 : 10 (2009)
35. Cruts,M., Brouwers,N., Van Broeckhoven,C.: The Alzheimer Disease & Frontotemporal
Dementia Mutation Database. Human Variome Project Meeting 2009 - Spotlight on
Neurogenetics, Honolulu Hawai, October 19 : 20 (2009)
36. de almeida Souza,L., Goethals,S., Jacobs,A., De Winter,V., Irobi,J., Timmerman,V.,
Janssens,S.: How do CMT-related mutations in HSPB1 affect its biochemical properties? Third
International Charcot-Marie-Tooth Consortium Meeting, Antwerp, Belgium, July 9-11 : Oral
(2009)
37. Deprez,L., Weckhuysen,S., Holmgren,P., Suls,A., Van Dyck,T., Goossens,D., Del-Favero,J.,
Janssen,A., Verhaert,K., Lagae,L., Van Paesschen,W., Jordanova,A., Yendle,S., Berkovic,S.F.,
Scheffer,I.E., Ceulemans,B., De Jonghe,P.: Broad clinical spectrum of early onset epileptic
encephalopathies associated with STXBP1 mutations. Annual Scientific IAP6/43 meeting,
University of Brussels (ULB), October 26 : 46 (2009)
38. Gijselinck,I., Engelborghs,S., Maes,G., Cuijt,I., Peeters,K., Mattheijssens,M., Joris,G., Cras,P.,
De Deyn,P., Kumar-Singh,S., Van Broeckhoven,C., Cruts,M., Martin,J-J.: A genome-wide
linkage study in a multiplex FTLD-ALS family identifies two loci at chromosomes 9 and 14.
Annual Scientific IAP6/43 meeting, University of Brussels (ULB), October 26 : 23 (2009)
Scientific Report Institute Born-Bunge 2010. Page 68
39. Goethals,S., Smits,V., Jacobs,A., Timmerman,V., Janssens,S.: Induction of TLR expression in
the peripheral nerve upon neurodegeneration. Third International Charcot-Marie-Tooth
Consortium Meeting, Antwerp, Belgium, July 9-11 : P51 (2009)
40. Gonçalves,R., Storkebaum,E., Godenschwege,T., Nangle,L., Mejia,M., Jacobs,A., Bosmans,I.,
Ooms,T., Yang,X-L, Schimmel,P., Norga,K., Timmerman,V., Callaerts,P., Jordanova,A., Van
Dijck,P.: Towards a better understanding of DI-CMTC, a contribution from Drosophila. Third
International Charcot-Marie-Tooth Consortium Meeting, Antwerp, Belgium, July 9-11 : Oral
(2009)
41. Guergueltcheva,V., Kilimov,N., Tournev,I., Fidani,L., Dimovski,A., Cherninkova,S., Baets,J.,
De Vriendt,E., Löfgren,A., Timmerman,V., De Jonghe,P., Jordanova,A.: Asp35Tyr mutation in
myelin protein zero leading to axonal Charcot-Marie-Tooth disease - Further data on phenotype
expression. Third International Charcot-Marie-Tooth Consortium Meeting, Antwerp, Belgium,
July 9-11 : P23 (2009)
42. Holmgren,A., Timmerman,V., Irobi,J.: Mutant HSPB8 and HSPB1 impairs formation of stable
neurofilament network. Third International Charcot-Marie-Tooth Consortium Meeting,
Antwerp, Belgium, July 9-11 : P40 (2009)
43. Irobi,J., Krishnan,J., de almeida Souza,L., Dierick,I., Ceuterick-de Groote,C., Van Den
Bosch,L., Timmermans,J-P., Robberecht,W., De Jonghe,P., Janssens,S., Timmerman,V.:
Mutant heat shock protein HSPB8 induces aggregation and a pro-apoptotic phenotype in distal
motor neuropathy. Annual Scientific IAP6/43 meeting, University of Brussels (ULB), October
26 : 26 (2009)
44. Kabzinska,D., Seeman,P., Barankova,L., Zimon,M., Baets,J., Jordanova,A., De Jonghe,P.,
Hausmanowa-Petrusewicz,I., Kochañski,A.: The spectrum of GDAP1 gene mutations and
phenotypes in Polish CMT4A families; evidence for a founder effect for the Leu239Phe
mutation. Third International Charcot-Marie-Tooth Consortium Meeting, Antwerp, Belgium,
July 9-11 : P46 (2009)
45. Kennerson,M., Nicholson,G., Kowalski,B., Chu,S., Takata,R., Speck-Martins,C., Baets,J.,
Timmerman,V., Kaler,S., Tang,J., Mercer,J., Llanos,R., De Jonghe,P., Shy,M., Garbern,J.:
Novel missense mutations in the Menkes disease copper transporter, ATP7A, cause isolated
progressive adult-onset distal motor neuropathy. 59th Meeting of the The American Society of
Human Genetics, Honolulu, Hawaii, October 20-24 : 21 (58) (2009)
46. Kennerson,M., Nicholson,G., Kowalski,B., Chu,S., Takata,R., Speck-Martins,C., Baets,J.,
Timmerman,V., Kaler,S., Tang,J., Mercer,J., Llanos,R., De Jonghe,P., Shy,M., Garbern,J.:
Mapping the gene for X-linked distal hereditary motor neuropathy: An update. Third
International Charcot-Marie-Tooth Consortium Meeting, Antwerp, Belgium, July 9-11 : Oral
(2009)
47. Kleinberger,G., Wils,H., Ponsaerts,P., Joris,G., Timmermans,J-P., Van Broeckhoven,C.,
Kumar-Singh,S.: Increased apoptosis in cortical cultures derived from progranulin knockout
mice. VIB Science Club Neurodegenerative Diseases II, Leuven, Belgium, October 30 : (2009)
48. Kleinberger,G., Wils,H., Ponsaerts,P., Joris,G., Timmermans,J-P., Van Broeckhoven,C.,
Kumar-Singh,S.: Increased apoptosis in cortical cultures derived from progranulin knockout
mice. Annual Scientific IAP6/43 meeting, University of Brussels (ULB), October 26 : 31
(2009)
49. Kumar-Singh,S., Wils,H., Kleinberger,G., Janssens,J., Pereson,S., Joris,G., Cuijt,I., Ceuterickde Groote,C., Van Broeckhoven,C.: Wild-type human TDP-43 overexpression in transgenic
mice causes motor neuron degeneration. Annual Scientific IAP6/43 meeting, University of
Brussels (ULB), October 26 : 2 (2009)
Scientific Report Institute Born-Bunge 2010. Page 69
50. Mazanec,R., Haberlová,J., Redlová,M., Irobi,J., Timmerman,V., Seeman,P.: Distal hereditary
motor neuropathy in a large Czech family - clinical and electrophysiological study. Third
International Charcot-Marie-Tooth Consortium Meeting, Antwerp, Belgium, July 9-11 : P39
(2009)
51. Meeus,B., Nuytemans,K., Crosiers,D., Engelborghs,S., Pals,P., Pickut,B., Peeters,K.,
Mattheijssens,M., Corsmit,E., Cras,P., De Deyn,P., Theuns,J., Van Broeckhoven,C.: No major
role for GIGYF2 in Parkinson disease etiology in Belgian patients. Genetic epidemiology of
Parkinson's Disease 4th Annual Meeting (GEO-PD), Tübingen, Germany July 6-8 : 25 (2009)
52. Meeus,B., Nuytemans,K., Crosiers,D., Engelborghs,S., Peeters,K., Mattheijssens,M., Elinck,E.,
Corsmit,E., De Deyn,P., Van Broeckhoven,C., Theuns,J.: Familial dementia with Lewy bodies
at 2q35-q36: no role for simple mutations. Annual Scientific IAP6/43 meeting, University of
Brussels (ULB), October 26 : 36 (2009)
53. Meeus,B., Nuytemans,K., Crosiers,D., Engelborghs,S., Peeters,K., Mattheijssens,M., Elinck,E.,
Corsmit,E., De Deyn,P., Van Broeckhoven,C., Theuns,J.: Familial dementia with Lewy bodies
at 2q35-q36: an extensive sequencing analysis. VIB Science Club Neurodegenerative Diseases
II, Leuven, Belgium, October 30 : (2009)
54. Nuytemans,K., Meeus,B., Crosiers,D., Brouwers,N., Bogaerts,V., Engelborghs,S., Pals,P.,
Pickut,B., Van den Broeck,M., Corsmit,E., Goossens,D., Del-Favero,J., Cras,P., De Deyn,P.,
Theuns,J., Van Broeckhoven,C.: Genetic etiology of Parkinson?s disease in the Belgian patient
group. Annual Scientific IAP6/43 meeting, University of Brussels (ULB), October 26 : 38
(2009)
55. Nuytemans,K., Meeus,B., Crosiers,D., Brouwers,N., Pals,P., Engelborghs,S., Pickut,B.,
Corsmit,E., Van den Broeck,M., Cras,P., De Deyn,P., Cruts,M., Van Broeckhoven,C.,
Theuns,J.: PDmutDB: A publicity available database of all reported variations in major
Parkinson genes. Genetic epidemiology of Parkinson's Disease 4th Annual Meeting (GEO-PD),
Tübingen, Germany July 6-8 : 29 (2009)
56. Pereson,S., Wils,H., Kleinberger,G., McGowan,E., Joris,G., Jucker,M., Van Dam,D.,
Deforce,D., Hutton,M., Van Broeckhoven,C., Kumar-Singh,S.: The role of progranulin in
Alzheimer disease. VIB Science Club Neurodegenerative Diseases II, Leuven, Belgium,
October 30 : (2009)
57. Pereson,S., Wils,H., Van Damme,O., Joris,G., Franck,F., Jucker,M., Van Dam,D., Van
Broeckhoven,C., Kumar-Singh,S.: Role of progranulin in an Alzheimer disease. Annual
Scientific IAP6/43 meeting, University of Brussels (ULB), October 26 : 12 (2009)
58. Reddel,S., Ouvrier,R., Nicholson,G., Dierick,I., Irobi,J., Timmerman,V., Ryan,M.M.:
Dominant congenital spinal muscular atrophy predominantly affecting the lower limbs: a
primary developmental deficiency of motor neurons? Third International Charcot-Marie-Tooth
Consortium Meeting, Antwerp, Belgium, July 9-11 : Oral (2009)
59. Rotthier,A., Baets,J., Jacobs,A., De Vriendt,E., Jordanova,A., De Jonghe,P., Timmerman,V.:
Mutation analysis of genes for hereditary sensory and autonomic neuropathies: Identification of
new mutations and a genotype-phenotype correlation study. Third International Charcot-MarieTooth Consortium Meeting, Antwerp, Belgium, July 9-11 : P37 (2009)
60. Rotthier,A., Baets,J., Jacobs,A., De Vriendt,E., Jordanova,A., De Jonghe,P., Timmerman,V.:
Mutation analysis of genes for hereditary sensory and autonomic neuropathies: Identification of
new mutations and a genotype-phenotype correlation study. Annual Scientific IAP6/43
meeting, University of Brussels (ULB), October 26 : 6 (2009)
Scientific Report Institute Born-Bunge 2010. Page 70
61. Rotthier,A., Baets,J., Jacobs,A., De Vriendt,E., Jordanova,A., De Jonghe,P., Timmerman,V.:
Mutation analysis of genes for hereditary sensory and autonomic neuropathies: identification of
new mutations and a genotype-phenotype correlation study. VIB Seminar 2009, Blankenberge,
Belgium, March 12 : P92 (2009)
62. Stendel,C., Roos,A., Battaloglu,E., Clayton-Smith,J., De Jonghe,P., Erdem,S., GabreëlsFesten,A., Hahn,A., Müller-Felber,W., Parman,Y., Planté-Bordeneuve,V., Rautenstrauss,B.,
Schröder,J.M., Straub,V., Takiyama,Y., Timmerman,V., Topaloglu,H., Urtizberea,A.,
Züchner,S., Weis,J., Zerres,K., Senderek,J.: A comprehensive molecular genetic workup for
autosomal recessive forms of Charcot-Marie-Tooth disease. Third International Charcot-MarieTooth Consortium Meeting, Antwerp, Belgium, July 9-11 : Oral (2009)
63. Van Avondt,K., Goethals,S., Jacobs,A., Timmerman,V., Janssens,S.: Induction of TLR
expression in the peripheral nerve upon neurodegeneration. VIB Seminar 2009, Blankenberge,
Belgium, March 12 : P72 (2009)
64. Van Langenhove,T., van der Zee,J., Sleegers,K., Engelborghs,S., Vandenberghe,R.,
Gijselinck,I., Van den Broeck,M., Mattheijssens,M., Peeters,K., De Deyn,P., Cruts,M., Van
Broeckhoven,C.: Genetic contribution of FUS to Frontotemporal Lobar Degeneration. VIB
Science Club Neurodegenerative Diseases II, Leuven, Belgium, October 30 : (2009)
65. Van Langenhove,T., van der Zee,J., Sleegers,K., Engelborghs,S., Vandenberghe,R.,
Gijselinck,I., Van den Broeck,M., Mattheijssens,M., Peeters,K., De Deyn,P., Cruts,M., Van
Broeckhoven,C.: Genetic contribution of FUS to Frontotemporal Lobar Degeneration. Annual
Scientific IAP6/43 meeting, University of Brussels (ULB), October 26 : 7 (2009)
66. Van Maldergem,L., Timmerman,V., De Jonghe,P.: Genealogical studies as a tool for
improvement of knowledge on MPZ Thr124Met axonal neuropathy Third International
Charcot-Marie-Tooth Consortium Meeting, Antwerp, Belgium, July 9-11 : P24 (2009)
67. van Paassen,B.W., van Ruissen,F., Bradley,E.J., Timmerman,V., De Jonghe,P., van der
Kooi,A.J., Baas,F.: Complement factor H and PMP22-related neuropathies. Third International
Charcot-Marie-Tooth Consortium Meeting, Antwerp, Belgium, July 9-11 : P52 (2009)
68. Weterman,M.A.J., Anthonellis,A., Züchner,S., Jordanova,A., De Jonghe,P., AuerGrumbach,M., Vance,J., Green,E.D., Timmerman,V., Bienfait,H.M.E., De Visser,M., Baas,F.:
Identification of a potentially pathogenic novel sequence alteration in the YARS gene. Third
International Charcot-Marie-Tooth Consortium Meeting, Antwerp, Belgium, July 9-11 : P50
(2009)
69. Wils,H., Kleinberger,G., Janssens,J., Pereson,S., Joris,G., Cuijt,I., Smits,V., Ceuterick-de
Groote,C., Van Broeckhoven,C., Kumar-Singh,S.: Biochemical characterization of FTLD-TDP
overexpression and knockout mouse models. VIB Science Club Neurodegenerative Diseases II,
Leuven, Belgium, October 30 : (2009)
70. Wils,H., Kleinberger,G., Janssens,J., Pereson,S., Joris,G., Cuijt,I., Ceuterick-de Groote,C., Van
Broeckhoven,C., Kumar-Singh,S.: Wild-type human TDP-43 overexpression in transgenic
mice causes an ALS-like motor neuron degeneration with associated neuronal inclusions.
Annual Scientific IAP6/43 meeting, University of Brussels (ULB), October 26 : 52 (2009)
71. Zhang,F., Khajavi,M., Towne,C.F., Batish,S.D., De Vriendt,E., De Jonghe,P.,
Vandenberghe,A., Palau,F., Van Maldergem,L., Timmerman,V., Lupski,J.: Nonrecurrent
genoic rearrangements associated with CMT1A or HNPP and their underlying mechanisms.
59th Meeting of the The American Society of Human Genetics, Honolulu, Hawaii, October 2024 : 407 (1365/W/Poster #1023) (2009)
Scientific Report Institute Born-Bunge 2010. Page 71
72. Zimon,M., Baets,J., De Vriendt,E., Deconinck,T, De Jonghe,P., Jordanova,A.: Large scale
genetic approach for the molecular characterization of autosomal-recessive Charcot-MarieTooth disease. Third International Charcot-Marie-Tooth Consortium Meeting, Antwerp,
Belgium, July 9-11 : P48 (2009)
73. Zimon,M., Baets,J., Dierick,I., De Vriendt,E., Deconinck,T, Jaakkola,E., Battaloglu,E.,
Guergueltcheva,V., Tournev,I., Sarafov,S., Fabrizi,G.-M., Timmerman,V., De Jonghe,P.,
Jordanova,A.: Novel mutations bring novel insight into GDAP1-associated CMT neuropathies.
Third International Charcot-Marie-Tooth Consortium Meeting, Antwerp, Belgium, July 9-11 :
P47 (2009)
74. Zimon,M., Baets,J., Dierick,I., De Vriendt,E., Deconinck,T, Jaakkola,E., Battaloglu,E.,
Guergueltcheva,V., Tournev,I., Sarafov,S., Fabrizi,G.-M., Timmerman,V., De Jonghe,P.,
Jordanova,A.: Novel mutations bring novel insight into GDAP1?associated CMT neuropathies.
Annual Scientific IAP6/43 meeting, University of Brussels (ULB), October 26 : 53 (2009)
75. Zimon,M., Baets,J., Dierick,I., De Vriendt,E., Deconinck,T, Timmerman,V., De Jonghe,P.,
Jordanova,A.: Novel mutations in GDAP1 causing both dominant and recessive CMT disease.
9th annual meeting of the Belgian Society of Human Genetics: Darwin's 200th Birthday, ULB,
Brussels, Belgium, February 13 : (2009)
2008
76. Bettens,K., Brouwers,N., Engelborghs,S., De Deyn,P., Van Broeckhoven,C., Sleegers,K.: The
neuronal sorting receptor SORL1 is genetically associated with increased risk for late-onset
Alzheimer disease in a Belgian population. XX International Congress of Genetics, Berlin,
Germany, July 12-17 : 151 (2008)
77. Bettens,K., Brouwers,N., Engelborghs,S., De Deyn,P., Van Broeckhoven,C., Sleegers,K.: The
neuronal sorting receptor SORL1 is genetically associated with increased risk for late-onset
Alzheimer disease in the Belgian population. Intracellular traffic and neurodegenerative
disorders, Paris, France, April 28 : (2008)
78. Bettens,K., Brouwers,N., Engelborghs,S., De Deyn,P., Van Broeckhoven,C., Sleegers,K.: The
neuronal sorting receptor SORL1 is genetically associated with increased risk for late-onset
Alzheimer disease in the Belgian population. VIB Seminar 2008, Blankenberge, Belgium,
March 6 : P85 (2008)
79. Brouwers,N., Sleegers,K., Engelborghs,S., Maurer-Stroh,S., Gijselinck,I., van der Zee,J.,
Pickut,B., Van den Broeck,M., Mattheijssens,M., Peeters,K., Schymkowitz,J., Rousseau,F.,
Martin,J-J., Cruts,M., De Deyn,P., Van Broeckhoven,C.: Genetic variability at the progranulin
locus contributes to risk for clinically diagnosed Alzheimer disease. Intracellular traffic and
neurodegenerative disorders, Paris, France, April 28 : (2008)
80. Claes,L., Deprez,L., Suls,A., Smets,K., Baets,J., Jansen,A., Van Dyck,T., Deconinck,T,
Löfgren,A., Vandenbroucke,A., Jordanova,A., De Jonghe,P.: Unraveling the spectrum of
epilepsy phenotypes caused by SCN1A mutations. VIB Seminar 2008, Blankenberge, Belgium,
March 6 : P87 (2008)
81. Dierick,I., Baets,J., Irobi,J., De Jonghe,P., Timmerman,V.: Mutation analysis of HSPB1,
BSCL2, GARS, DCTN1, SETX and VAPB in a large cohort of patients with distal (hereditary)
motor neuropathy. VIB Seminar 2008, Blankenberge, Belgium, March 6 : P88 (2008)
82. Gijselinck,I., Maes,G., van der Zee,J., Cuijt,I., Peeters,K., Mattheijssens,M., Van
Broeckhoven,C., Cruts,M.: Identification of a novel chromosomal locus in a Belgian FTLDMND family. Human Genome Meeting - HGM 2008, Hyderabad, India, September 27-30 : 73
(2008)
Scientific Report Institute Born-Bunge 2010. Page 72
83. Irobi,J., Krishnan,J., de almeida Souza,L., Dierick,I., Janssens,S., Timmermans,J-P., Ceuterickde Groote,C., Van Den Bosch,L., Robberecht,W., De Jonghe,P., Timmerman,V.: Distal
hereditary motor neuropathy caused by mutant HSPB8 reduced cell viability and induced
protein aggregation. VIB Seminar 2008, Blankenberge, Belgium, March 6 : P10 (2008)
84. Jordanova,A.: Current trends in human molecular genetics: look to the future but learn from the
past! VIB Seminar 2008, Blankenberge, Belgium, March 6 : Keynote: 8 (2008)
85. Kleinberger,G., Wils,H., Joris,G., De Vijlder,T., Ponsaerts,P., Witters,E., Van Broeckhoven,C.,
Kumar-Singh,S.: Progranulin (GRN) is directly involved in cell proliferation but not in
caspase-activation in glial and non-glial cells. VIB Seminar 2008, Blankenberge, Belgium,
March 6 : P28 (2008)
86. Meeus,B., Bogaerts,V., Engelborghs,S., Nuytemans,K., Pickut,B., Peeters,K., Martin,J-J., De
Deyn,P., Van Broeckhoven,C., Theuns,J.: The search for the first DLB gene on 2q35-q36. XX
International Congress of Genetics, Berlin, Germany, July 12-17 : 160 (2008)
87. Meeus,B., Nuytemans,K., Engelborghs,S., Pickut,B., Peeters,K., Martin,J-J., De Deyn,P., Van
Broeckhoven,C., Theuns,J.: The search for the first gene at 2q35-q36 for dementia with Lewy
bodies. Genetic Epidemiology of Parkinson's Disease 4th Annual Meeting (GEO-PD),
Trondheim, Norway, June 9-11 : No7 (2008)
88. Nuytemans,K., Brouwers,N., Meeus,B., Pals,P., Engelborghs,S., Pickut,B., Bogaerts,V.,
Corsmit,E., Van den Broeck,M., De Deyn,P., Theuns,J., Van Broeckhoven,C.: Genetic
characterization of a Belgian Parkinson's disease population: contribution of copy number
variations and simple mutations. Genetic Epidemiology of Parkinson's Disease 4th Annual
Meeting (GEO-PD), Trondheim, Norway, June 9-11 : No6 (2008)
89. Pereson,S., Vandewoestyne,M., Van Broeck,B., Cuijt,I., Peeters,E., Ceuterick,C.,
McGowan,E., Jucker,M., Van Broeckhoven,C., Deforce,D., Kumar-Singh,S.: Differential
expression analysis to identify vascular abnormalities in Alzheimer disease mouse models.
Intracellular traffic and neurodegenerative disorders, Paris, France, April 28 : (2008)
90. Sleegers,K., Meeus,B., Brouwers,N., Bettens,K., Nyberg,L., Adolfsson,A., Nilsson,L-G., Van
Broeckhoven,C.: Genetic variability in progranulin and episodic memory. Biology of Cognition
Annual Meeting, Chantilly, France, October 16-18 : 40 (2008)
91. Suls,A., Dedeken,P., Goffin,K., Van Esch,H., Dupont,P., Cassiman,D., Kempfle,J.,
Wuttke,T.V., Weber,Y., Lerche,H., Afawi,Z., Korczyn,A.D., Berkovic,S.F., Vandenberghe,W.,
Ekstein,D., Kivity,S., Ryvlin,P., Claes,L., Deprez,L., Maljevic,S., Vargas,A., Van Dyck,T.,
Goossens,D., Del-Favero,J., Van Laere,K., De Jonghe,P., Van Paesschen,W.: Paroxysmal
exercise-induced dyskinesia and epilepsy: delineation of the genetic defect and functional
imaging. VIB Seminar 2008, Blankenberge, Belgium, March 6 : T16 (2008)
92. Van Broeckhoven,C.: Progranulin and neurodegeneration: A new pathway to treatment? 7the
Research Day, University of Maastricht, April 11 : 13 (2008)
c3 – octrooien
7. DOCTORATEN
Finished PhD projects
Van Broeck Bianca (21/04/2008)
Loss-of-function mechanisms and intraneuronal Aβ in cellular and mouse models of Alzheimer
disease.
Promotors: S. Kumar-Singh, C. Van Broeckhoven
Scientific Report Institute Born-Bunge 2010. Page 73
Gijselinck Ilse (8/09/2008)
Molecular genomics of tau-negative, ubiquitin-positive frontotemporal lobar degeneration.
Promotors: C. Van Broeckhoven, M. Cruts
Brouwers Nathalie (15/12/2008)
Molecular genetic analysis of Alzheimer disease
Promotor: C. Van Broeckhoven
Pirici Daniel (20/03/2009)
Molecular mechanisms of extracellular and intracellular proteinopathy in Alzheimer’s disease and
frontotemporal dementia
Promotors: S. Kumar-Singh, C. Van Broeckhoven
Suls Arvid (18/05/2009)
Novel insights and broadening of the phenotypic spectrum for epilepsy caused by mutations in the
SCN1A and SLC2A1 genes
Promotor: P. De Jonge
Nuytemans Karen (14/12/2009)
Identification of novel genetic factors for Parkinson's disease
Promotor: C. Van Broeckhoven, co-promotor: Jessie Theuns
Brouns Raf (2/02/2010)
The predictive value of biochemical parameters among wich amino acids and amino acid analogues
in acute ischemic stroke
Promotors: P. P. De Deyn, B. Marescau
Bettens Karolien (21/10/2010)
Molecular genetic analysis of Alzheimer dementia
Promotors: C. Van Broeckhvoen & K. Sleegers
Wils Hans (7/12/ 2010)
Elucidation of the role of progranulin (PGRN) in frontotemporal dementia (FTD) with mouse
models
Promotors: C. Van Broeckhoven & S. Kumar-Singh
Rotthier Annelies (8/12/ 2010)
Molecular genetic analysis of genes for inherited axonal peripheral neuropathies
Promotors: V. Timmerman
Gonçalves Ricardo (21/12/ 2010)
Molecular Genetics and Biology of Intermediate Charcot-Marie-Tooth neuropathy
Promotors: V. Timmerman & A. Jordanova
Sheorajpanday Rishi (23/11/2010)
Additional value of quantitative EEG in ischemic CVA.
Promotor: P.P. De Deyn
Gebruers Nick (27/01/2011)
Secondary edema in patients with stroke: actigraphic and volumetric evaluation
Promotor: P.P. De Deyn; Co-promotors: S. Engelborghs and S. Truijen
Scientific Report Institute Born-Bunge 2010. Page 74
Ongoing PhD projects
Baets Jonathan
Clinical, electrophysiological and molecular genetic characterization of HMSN type II and
intermediate type of CMT
Promotor: P. De Jonghe
Crosiers David
Clinical and genetic epidemiology of Parkinson's disease: focus on disease progression and nonmotor symptoms
Promotor: P. Cras, Co-promotor: C. Van Broeckhoven
Geerts Elly
Sleep and circadian rhythm disturbances in Alzheimer’s disease: the effect of pharmacological and
non-pharmacological manipulations in preclinical and clinical settings.
Promotor: P.P. De Deyn; Co-promotor: D. Van Dam
Janssens Jonathan
Characterization of new mice models for frontal lobe degeneration (FTLD) and amyotrophic lateral
sclerosis (ALS)
Promotor: C. Van Broeckhoven
Janssens Katrien
Functional implications of RAB7 mutations in the pathogenesis of an ulcero-mutilating neuropathy
Promotor: V. Timmerman
Janssen Leen
Oplosbare amyloïd-beta oligomeren en cell-cycle events in het APP23-muismodel: waar, wanneer,
hun verband met elkaar en hun rol in de pathologie van de ziekte van Alzheimer.
Promotor: P.P. De Deyn; Co-promotor: D. Van Dam
Kleinberger Gernot
Elucidation of the role of progranulin in frontotemporal dementia
Promotors: C. Van Broeckhoven, S. Kumar-Singh
Holmgren Anne
Molecular biological research of HSPB8 mutations in relation to inherited motorneuron diseases',
Promotor: V. Timmerman, Co-promotor: J. Irobi
Holmgren Philip
Molecular genetic analysis of idiopathic epilepsies: gene identification through array Comparative
Genomic Hybridazation (aCGH)
Promotors: P. De Jonghe & A. Jordanova
Le Bastard Nathalie
Characterization and validation of biological markers in dementia and mild cognitive impairment.
Promotor: P.P. De Deyn; Co-promotor: S. Engelborghs
Meeus Bram
Identification and characterization of new causal genes and risk factors for 'Lewy body' brain
diseases
Promotors: C. Van Broeckhoven, J. Theuns
Scientific Report Institute Born-Bunge 2010. Page 75
Pereson Sandra
Mechanisms of dense plaque formation in Alzheimer’s disease
Promotors: C. Van Broeckhoven, S. Kumar-Singh
Philtjens Stéphanie
New causal genes and risk factors for FTLD
Promotor: C. Van Broeckhoven, M. Cruts
Van Cauwenberghe Caroline
Neuropatholgical image analysis in Alzheimer's disease (AD) patients and in AD mouse models
treated with anti-amyloidotic and vasogenic compounds
Promotors: C. Van Broeckhoven, K. Sleegers
Van der Mussele Stefan
Karakterisatie van gedrag bij Mild Cognitive Impairment (MCI)
Promotors: P.P. De Deyn, S. Engelborghs
Van Dijck Annemie
Massaspectrometrische en functionele analyse van het neuropeptidoom in transgene muismodellen
voor de ziekte van Alzheimer.
Promotor: P.P. De Deyn; Co-promotor: D. Van Dam
Van Langenhove Tim
Molecular genetic research towards the complex genetics of frontotemporal lobe dementia
Promotor: C. Van Broeckhoven
Vermeiren Yannick
Neurochemische karakterisatie van gedragsstoornissen
characterization of behavioral disturbances in dementia.
Promotors: P.P. De Deyn; S. Engelborghs
bij
dementie
–
Neurochemical
Verstraeten Aline
Identification and characterization of novel causal genes for Lewy Body disorders using nextgeneration sequencing
Promotors: C. Van Broeckhoven, J. Theuns
Wostyn Peter
The role of reduced cerebrospinal fluid pressure in the pathogenesis of glaucoma in patients with
Alzheimer’s disease
Promotors: P.P. De Deyn, K. Oudenaert
Ydens Elke
Negatieve regulatie van de aangeboren immuunrespons in de perifere zenuw', 'Negative regulation
of congenital immune respons in peripheral nerves
Promotor: V. Timmerman
Zimon Magdalena
Large scale genetic approach for the molecular characterization of autosomal-recessive CharcotMarie-Tooth disease
Promotors: A. Jordanova, P. De Jonghe
Scientific Report Institute Born-Bunge 2010. Page 76